The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index; 12 of the 27 sources its claims cite were checked for support.
The structure of human thyroglobulin
Open accessAbstract
Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates1,2. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis3. Tyrosine proximity within TG is thought to enable the coupling reaction but hormonogenic tyrosines have not been clearly identified, and the lack of a three-dimensional structure of TG has prevented mechanistic understanding4. Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 Å, determined by cryo-electron microscopy. We identified all of the hormonogenic tyrosine pairs in the structure, and verified them using site-directed mutagenesis and in vitro hormone-production assays using human TG expressed in HEK293T cells. Our analysis revealed that the proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. We transferred the reaction sites from TG to an engineered tyrosine donor–acceptor pair in the unrelated bacterial maltose-binding protein (MBP), which yielded hormone production with an efficiency comparable to that of TG. Our study provides a framework to further understand the production and regulation of thyroid hormones. The cryo-electron microscopy structure of human thyroglobulin reveals that proximity, flexibility and solvent exposure are key characteristics of its hormonogenic tyrosine pairs, and provides a framework for understanding the formation of thyroid hormones.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
The paper reports the cryo-EM structure of full-length human thyroglobulin at ~3.5 Å and identifies/validates its four hormonogenic sites and five donor tyrosines. It shows that proximity, flexibility, solvent exposure, and roughly antiparallel orientation enable T4 synthesis, and transfers a functional hormonogenic site into engineered maltose binding protein.
Key findings
- The human thyroglobulin dimer structure was determined at ~3.5 Å resolution (eTG C2 map 3.39 Å; rTG expanded map 3.67 Å), with a bilobed shape of 120 × 235 Å, a dimer interface of 29,350 Ų, and an atomic model covering 93% of 2,749 amino acids (2,569 protein residues; PDB 6SCJ).
- Four hormonogenic acceptor tyrosines were identified—Y24 (Site A), Y2573 (Site B), Y2766 (Site C), and Y1310 (Site D)—with five donor tyrosines: Y234 and Y149 for Site A, Y2540 for Site B, Y2766 for Site C, and Y108 for Site D. Mutating all acceptors abolished T4 synthesis; mutating all five donors gave no significant T4 formation, and Site A was confirmed to have two donors.
- TG synthesises seven T4 molecules per dimer: two each of Sites A, B, and D, and one Site C. Key requirements for hormonogenesis are solvent exposure, proximity, roughly antiparallel orientation, and high mobility; a conserved acidic residue precedes the acceptor, and D1309 was essential for Site D while K1415 was not.
- An engineered MBP variant with a C-terminal SGSDYS insert (C-ins2) produced T4 at levels comparable to a single TG site. Crosslinking mass spectrometry validated the architecture, no inter-subunit disulfides were found, and 12 previously predicted N-linked GlcNAc plus four new sites (N110, N484, N1869, N2122) were resolved; glycan N2013 mediates NTD–CTD contact.
Methods
- Recombinant full-length human TG was expressed in HEK293T cells; endogenous TG was purified from goitrous human thyroid glands. Cryo-EM used a Titan Krios G2 with K2 Summit detector, C2 and symmetry-expanded refinements, and model building combined de novo and homology modelling.
- Site-directed mutagenesis replaced acceptor or donor tyrosines with phenylalanines. In vitro iodination used KI, glucose/glucose oxidase, and lactoperoxidase or thyroid peroxidase; T4 and T3 were measured by commercial ELISA. MBP variants were engineered and assayed similarly.
- Cryo-EM datasets: eTG 422,087 initial and 181,830 final particles; rTG 240,194 initial and 151,601 final particles. Crosslinking mass spectrometry used BS3, tryptic digestion, SEC enrichment, and LC-MS/MS with Xi search at 2% residue-pair FDR.
Limitations
- Stated: map resolution is non-uniform, with central ChEL regions at ~3 Å but peripheral Arm regions at ~6 Å; the model has variable local quality. The NTD is partially flexible, Y24 is partially disordered, residues 24–29 were built tentatively as poly-alanine, and Y2766 was not resolved in the maps. Only T4, not T3, was detected under the in vitro conditions.
- Stated: endogenous TG was partly iodinated and partially degraded; recombinant TG was non-iodinated. The in vitro assay relies on LPO/TPO and ELISA detection rather than the native thyroid environment.
- Evident from the text: the atomic model covers 93% of the 2,749 amino acids, leaving some regions unmodelled; side-chain placements at hormonogenic sites are difficult due to conformational disorder; and the MBP engineering test is limited to a small set of designed variants.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
54 Own result · 17 Own interpretation · 15 Own method · 10 No full text of the sources · 9 No basis given · 5 Partly supported · 4 Supported · 1 Supported so far · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hormonogenic tyrosines have not been clearly identified and the lack of a three-dimensional structure of TG has prevented mechanistic understanding4.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Partly supportedcites [4] Cahnmann, H. J., Pommier, J. & Nunez, J. Spatial requirement for coupling of iodotyrosine residues to form thyroid hormones. Proc. Natl Acad. Sci. USA 74, 5333–5335 (1977). sourceExperimental — accuracy not yet measured
The introductory passage (page unavailable) says thyroglobulin’s primary sequence was unknown and the molecule was too complex to study the factors governing spatial alignment, prompting the authors to use simpler models. It does not specifically say that the lack of a three-dimensional structure prevented mechanistic understanding more broadly. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, in the context of the thyroid gland and the iodine cycle in vertebrates, TG's structure effectively combines hormonogenesis with iodination of many other solvent exposed tyrosine residues for iodine storage21,13.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Lamas, L., Anderson, P. C., Foxy, J. W. & Dunn, J. T. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J. Biol. Chem. 264, 13541–13545 (1989). source
- Partly supportedcites [13] Dedieu, A., Gaillard, J.-C., Pourcher, T., Darrouzet, E. & Armengaud, J. Revisiting iodination sites in thyroglobulin with an organ-oriented shotgun strategy. J. Biol. Chem. 286, 259–269 (2011). sourceExperimental — accuracy not yet measured
The Abstract describes Tg as both a scaffold for thyroid hormonogenesis and an iodine reservoir. The Discussion reports many iodinated tyrosines but only a few hormonogenic sites, and suggests that the additional iodination probably stores iodine. The paper does not establish that those other residues are solvent-exposed; its direct findings are from mouse Tg rather than vertebrates generally. Page numbers are unavailable in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“At Site C, Y2766, not resolved in our maps, probably acts both as donor and acceptor across the C2 dimer axis19.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Supportedcites [19] Citterio, C. E., Morishita, Y., Dakka, N., Veluswamy, B. & Arvan, P. Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. J. Biol. Chem. 293, 4860–4869 (2018). source
The Discussion (page not available) proposes that the conserved antepenultimate tyrosine can form T3 by acting as an MIT donor in one thyroglobulin monomer and a DIT acceptor in the other. The source numbers this residue Tyr2744 in mouse thyroglobulin; the statement about what was resolved in “our maps” concerns the citing authors’ own maps. (LLM, conf=0.87)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Most of TG's disulfide bonds show clear EM density in our maps (Extended Data Figure 5a) and we found no inter-subunit disulfide bonds, in agreement with previous observations that TG is a non-covalent dimer19.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Supportedcites [19] Citterio, C. E., Morishita, Y., Dakka, N., Veluswamy, B. & Arvan, P. Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. J. Biol. Chem. 293, 4860–4869 (2018). source
The paper’s introductory passage states that TG self-associates noncovalently into a dimer shortly after synthesis. It also notes that inter-monomer covalent bonds can form later upon oxidation in thyroid follicles; that qualification does not negate the cited description of TG dimerization. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only T4 was produced in detectable amounts in our in vitro TH production assay.”
§ The structure of human thyroglobulin > Methods > T4 and T3 ELISA
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showing the absence of higher-order structures caused by unwanted inter-dimer crosslinks.”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In TG there are no more than five pairs that are exposed and in < 15 Å proximity at the same time”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In MBP only one pair closer than 15 Å is sufficiently exposed to be a candidate for hormonogenesis.”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unmodified MBP's T4 hormone production was only measurable at the higher concentration.”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
In the paper
“We inspected our structure within a 15 Å radius of the reported acceptor tyrosines (designated Sites A-D)21 and identified putative donor tyrosines (Figure 2a).”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Lamas, L., Anderson, P. C., Foxy, J. W. & Dunn, J. T. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J. Biol. Chem. 264, 13541–13545 (1989). source
hedgedn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 21
- It may state two separate claims as one. 39
Every source the paper cites for this claim was checked and supports it.
In the paper
“Finally, with our ELISA we could also obtain modest T4 synthesis from random tyrosine copolymers, as previously reported4 (Extended Data Figure 6e).”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Supportedcites [4] Cahnmann, H. J., Pommier, J. & Nunez, J. Spatial requirement for coupling of iodotyrosine residues to form thyroid hormones. Proc. Natl Acad. Sci. USA 74, 5333–5335 (1977). source
The Results and Discussion report thyroxine formation from a linear random tyrosine–lysine copolymer, with coupling yields of 11% using lactoperoxidase and 15% using thyroid peroxidase. The ELISA is the citing authors’ method, not a method attributed to this source. (LLM, conf=0.92)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TG, a protein dimer of 600 kDa, has an unusually high number of ~ 60 disulfide bonds per monomer and 17 glycosylation sites, which confer remarkable stability and solubility to the protein1,2,9.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Partly supportedcites [1] Di Jeso, B. & Arvan, P. Thyroglobulin from molecular and cellular biology to clinical endocrinology. Endocr. Rev. 37, 2–36 (2016). sourceExperimental — accuracy not yet measured
The Introduction reports about 60 disulfide bonds per Tg monomer, and section V identifies Tg as a homodimer, but gives its mass as 660 kDa rather than 600 kDa. The glycan-dependent oxidoreductase section reports 10–15 N-linked oligosaccharides per monomer, not 17; section VI says glycans generally increase protein solubility, but does not establish that the claimed structural features confer remarkable stability and solubility on Tg. (LLM, conf=0.90)
- Partly supportedcites [2] Citterio, C. E., Targovnik, H. M. & Arvan, P. The role of thyroglobulin in thyroid hormonogenesis. Nat. Rev. Endocrinol. 15, 323–338 (2019). sourceExperimental — accuracy not yet measured
A Results passage in the indexed copy describes TG as a homodimeric glycoprotein, supporting the dimer description. The passages do not give a 600 kDa mass, approximately 60 disulfide bonds per monomer, 17 glycosylation sites, or their proposed effect on stability and solubility. The indexed text also appears to contain a different article from the cited review, so those details cannot be verified against it. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [9] Heidelberger, M. The molecular weight of thyroglobulin. Science 80, 414 (1934). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hormonogenic tyrosines have not been clearly identified and the lack of a three-dimensional structure of TG has prevented mechanistic understanding4.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Partly supportedcites [4] Cahnmann, H. J., Pommier, J. & Nunez, J. Spatial requirement for coupling of iodotyrosine residues to form thyroid hormones. Proc. Natl Acad. Sci. USA 74, 5333–5335 (1977). sourceExperimental — accuracy not yet measured
The introductory passage (page not supplied) says thyroglobulin’s primary sequence was unknown and that its complexity prevented study of factors governing coupling. This is consistent with hormonogenic tyrosines not being clearly identified, but the paper does not specifically attribute the mechanistic limitation to a lack of three-dimensional structure. (LLM, conf=0.82)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Approximately 5% of the world's human population suffer from thyroid diseases, but the molecular events behind TH synthesis are yet to be completely understood6.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Could not verifycites [6] Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018). sourceExperimental — accuracy not yet measured
The Introduction discusses thyroid dysfunction and hormone measurement, but not whether the molecular events of thyroid hormone synthesis are fully understood. A search for synthesis found a reference to a drug inhibiting synthesis, not a statement about gaps in understanding; searches for biosynthesis and molecular mechanisms likewise did not establish the claim. The indexed passages provide no page numbers. (LLM, conf=0.74)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“As shown in Figure 2c, when we mutated all acceptors (Y24, Y2573, Y2766 and Y1310)21,13 we observed no T4 synthesis, demonstrating that there are no more than four significant hormonogenic sites in TG.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Lamas, L., Anderson, P. C., Foxy, J. W. & Dunn, J. T. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J. Biol. Chem. 264, 13541–13545 (1989). source
- Supportedcites [13] Dedieu, A., Gaillard, J.-C., Pourcher, T., Darrouzet, E. & Armengaud, J. Revisiting iodination sites in thyroglobulin with an organ-oriented shotgun strategy. J. Biol. Chem. 286, 259–269 (2011). source
The citation follows the list of acceptor sites; the mutation experiment and its conclusion are presented as the citing authors’ own results. The Discussion (page unavailable) identifies four corresponding hormonogenic sites in mouse Tg, while the identification section reports T4 at three of them. The source uses mouse residue numbers rather than the citing sentence’s numbering. (LLM, conf=0.84)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Mutating a tyrosine to phenylalanine completely abolishes its ability to act as a hormonogenic donor or acceptor.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Most of TG's disulfide bonds show clear EM density in our maps (Extended Data Figure 5a) and we found no inter-subunit disulfide bonds, in agreement with previous observations that TG is a non-covalent dimer19.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Supportedcites [19] Citterio, C. E., Morishita, Y., Dakka, N., Veluswamy, B. & Arvan, P. Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. J. Biol. Chem. 293, 4860–4869 (2018). source
The paper’s introductory passage states that TG self-associates noncovalently into a dimer shortly after synthesis, supporting the point attached to citation 19. The EM density and absence of inter-subunit bonds in the citing authors’ maps are their own findings, not findings attributed to this source. The same passage notes that inter-monomer disulfide bonds can form later upon oxidation. (LLM, conf=0.90)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Mass spectrometry analyses of thyroid-extracted TG have identified four or more acceptor tyrosines, but the position of the donors has remained unclear13.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Partly supportedcites [13] Dedieu, A., Gaillard, J.-C., Pourcher, T., Darrouzet, E. & Armengaud, J. Revisiting iodination sites in thyroglobulin with an organ-oriented shotgun strategy. J. Biol. Chem. 286, 259–269 (2011). sourceExperimental — accuracy not yet measured
The Identification of Iodination Sites section identifies four distinct T3 or T4 acceptor positions: Tyr 25, 993, 1310, and 2572. But the Fate of the Lost Side Chain section identifies two donor positions, Tyr 259 and Tyr 2539, so the claim that donor positions remained unclear does not describe this study's findings. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Resolved Sites A, B and D do not show obvious structural similarity and active tyrosines are in solvent accessible and flexible regions (Figure 2a, Extended Data Figure 7a,c).”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, we showed that all acceptor mutants with one hormonogenic site active at a time (Figure 3a) contribute to hormone formation and the sum of the concentrations measured individually recapitulates the total T4 amount produced by unmodified rTG.”
§ The structure of human thyroglobulin > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The four TG hormonogenic sites contribute independently to total T4 production, so their individual activities can be summed.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When all five proposed donors were mutated, no significant T4 formation could be detected, confirming that Site A indeed has two donor tyrosines: Y234 and Y149.”
§ The structure of human thyroglobulin > Abstract
boosteddirectn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Mutating a tyrosine to phenylalanine completely abolishes its ability to act as a hormonogenic donor or acceptor.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the TG monomer, the globular NTD is connected to the Core region via a linker (residues 610-620), crossing the central dimer interface and it is partially flexible (Extended Data Figure 2f).”
§ The structure of human thyroglobulin > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The Core contains two triplets of type-1 repeats (domain H with a very large insertion), separated by domain I, located near the C2 axis.”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lysozyme (some tyrosines), SaFtsZ (no tyrosines) and T3 produce no T4 signal.”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using our reaction conditions, we could only detect significant production of T4, but not of T3 (Extended Data Figure 6f-g).”
§ The structure of human thyroglobulin > Abstract
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
In the paper
“The heme occupancy of TPO was estimated by measuring the ratio of absorbance at 412 nm and 280 nm which was 0.2, which roughly equates to 20% occupancy30.”
§ The structure of human thyroglobulin > Methods > Proteins, protein expression and purification
What the sources say
- Not checked — no full text of the sourcecites [30] Guo, J., McLachlan, S. M., Hutchison, S. & Rapoport, B. The greater glycan content of recombinant human thyroid peroxidase of mammalian than of insect cell origin facilitates purification to homogeneity of enzymatically protein remaining soluble at high concentration. Endocrinology 139, 999–1005 (1998). source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Because in Sites A, B and D the donor backbone conformation is constrained within secondary structure elements, whereas the acceptor is in more flexible regions, the acidic Asp or Glu residues (pointing towards the solvent) could play a role in orienting the following acceptor towards the more rigid donor.”
§ The structure of human thyroglobulin > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The Flap extends along the minor axis of the molecule with the M domain protruding at the opposite side of the NTD and folding back onto the Arm region.”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The central regions of the maps, corresponding to the C-terminal ChEL domains, were well defined (~3 Å in resolution), whereas peripheral regions corresponding to the Arms were noisy and at lower resolutions (~ 6 Å).”
§ The structure of human thyroglobulin > Methods > Cryo-EM image processing
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“We resolved 12 previously predicted N-linked GlcNac in our maps, and four that had not been identified, at N110, N484, N1869 and N212220 (Extended Data Table 3).”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [20] Yang, S.-X., Pollock, H. G. & Rawitch, A. B. Glycosylation in human thyroglobulin: location of the N-linked oligosaccharide units and comparison with bovine thyroglobulin. Arch. Biochem. Biophys. 327, 61–70 (1996). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within the overall TG structure, Site A is located in the NTD, Site B in the CTD, Site C is at the C-terminus across the C2 dimer interface and Site D bridges the NTD and Flap (M domain) of the other subunit in the dimer (Figure 2b).”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Following the domain arrangement in the context of TG's 3D structure, we defined five TG regions: NTD (N-terminal domain), Core, Flap, Arm and CTD (C-terminal domain), as indicated in Figures 1a-b.”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found it contains some T4, as measured by using our T4-ELISA, but not T3 (Extended Data Figure 6).”
§ The structure of human thyroglobulin > Methods > Proteins, protein expression and purification
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The resolution of the map is non-uniform and consequently the model has variable quality depending on the map region.”
§ The structure of human thyroglobulin > Methods > Model building
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In cryo-EM, TG has a bilobed shape with average dimensions of 120 x 235 Å, which correlate well with previously reported negative staining EM data15.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [15] Berg, G., Björkman, U. & Ekholm, R. The structure of newly synthesized intracellular thyroglobulin molecules. Mol. Cell. Endocrinol. 20, 87–98 (1980). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There is no preceding acidic residue in the C-terminal Site C, where both acceptor and donor (Y2766 from the two chains of the dimer) are in unstructured regions with higher intrinsic flexibility.”
§ The structure of human thyroglobulin > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, TG's structure appears entangled and revolves around the central ChEL dimer that interacts with different regions of the Arm and the Core of the same chain and, via the E domain, with the NTD of the other chain.”
§ The structure of human thyroglobulin > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Core is then connected to the Flap region, which is composed of two Ig-like domains, M and N.”
§ The structure of human thyroglobulin > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is also partially degraded, as shown by SDS-PAGE (Extended Data Figure 2a).”
§ The structure of human thyroglobulin > Methods > Proteins, protein expression and purification
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By mutagenesis of Site D, we showed that K1415 is not relevant, but D1309 is essential for hormonogenesis (Extended Data Figure 6d).”
§ The structure of human thyroglobulin > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Mutating a tyrosine to phenylalanine completely abolishes its ability to act as a hormonogenic donor or acceptor.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“LPO is as active as TPO, taking the reduced 20% heme content in our TPO into account.”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The best final maps we used for model building were the C2 map from the eTG dataset (overall 3.39 Å resolution) and the expanded map from the rTG dataset (overall 3.67 Å resolution).”
§ The structure of human thyroglobulin > Methods > Cryo-EM image processing
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showing conformational disorder within the hormonogenic sites, making precise side chain placements difficult, but the backbone positions are resolved (rTG map).”
§ The structure of human thyroglobulin > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This yielded calibration curves similar to the ones provided by the manufacturer, and also showed good dynamic range (Extended Data Figure 6).”
§ The structure of human thyroglobulin > Methods > T4 and T3 ELISA
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, the glycans linked to N2013 mediate the contact between the NTD and CTD and might contribute to the dimer stability (Extended Data Figure 5b & f, Supplementary Video 1).”
§ The structure of human thyroglobulin > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The C-ins1 variant, producing a putative tyrosine pair with Y341, also showed low activity, possibly because the added linker was designed to be too short for the two tyrosines to come into proximity.”
§ The structure of human thyroglobulin > Abstract
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, TG likely contains four hormonogenic acceptor tyrosines and five donor tyrosines.”
§ The structure of human thyroglobulin > Abstract
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that the involvement of glycans in TG dimer formation as revealed by the structure might explain the poor expression yields of thyroglobulin when produced in expression systems with reduced/altered glycosylation, such as insect cells, HEK293S GnT1-/- cells or HEK293T cells in the presence of kifunensine (data not shown).”
§ The structure of human thyroglobulin > Methods > Proteins, protein expression and purification
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The solvent exposure of tyrosines is presumably compensated by the exceptional solubility and stability that allows TG to persist at high concentrations in the harsh environment of the colloid.”
§ The structure of human thyroglobulin > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Moreover, the complexity of the TG molecule might fulfil further important roles in endocytosis, regulation of the T3/T4 ratio, TG proteolytic processing and in the trafficking to lysosomes25,26.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [25] Botta, R. et al. Sortilin is a putative postendocytic receptor of thyroglobulin. Endocrinology 150, 509–518 (2009). source
- Not checked — no full text of the sourcecites [26] Weber, J. et al. Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland. Eur. J. Cell Biol. 96, 440–456 (2017). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the overall resolution of the expanded and re-centred map was very similar to the C2 counterpart, the local resolution and continuity of the density in the Arm region was significantly improved (Extended Data Figure 2e).”
§ The structure of human thyroglobulin > Methods > Cryo-EM image processing
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that TG synthesises seven molecules of T4 per dimer, since each TG dimer contains two sites (one per monomer) of A, B and D and only one Site C.”
§ The structure of human thyroglobulin > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The four TG hormonogenic sites contribute independently to total T4 production, so their individual activities can be summed.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Molprobity score (percentile) | 1.85 (83rd)”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nature has selected the complex and large scaffold of the TG dimer to synthesise only seven molecules of hormones, using a chemical reaction involving radicals that could be carried out by unfolded peptides or other less complex proteins.”
§ The structure of human thyroglobulin > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the reaction mechanism of T4 synthesis from polypeptide chains remains to be established in more detail, four features seem to be crucial for hormonogenesis: tyrosine pairs must be solvent exposed to be iodinated, in proximity and in roughly antiparallel orientation, and in highly mobile regions of the protein in order to allow the significant bond rearrangement resulting in T4 synthesis.”
§ The structure of human thyroglobulin > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We attribute this basal activity to the Y171/Y176 pair since it could be suppressed by introducing a Y171A mutation.”
§ The structure of human thyroglobulin > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The correct assignment of the polypeptide chain register was often helped by the presence of large aromatic side chains and disulfide bond pairs, as well as the presence of glycosylation sites at Asn residues”
§ The structure of human thyroglobulin > Methods > Model building
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“eTG presumably contains already reacted tyrosine side chains.”
§ The structure of human thyroglobulin > Extended Data
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Residues 24 (acceptor Site A) to 29 were built tentatively into a map filtered to lower resolution using MAIN score map density modification procedure39, however their coordinates are only indicative and hence are included in the model as poly-alanine”
§ The structure of human thyroglobulin > Methods > Model building
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Disallowed (%) | 0”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Hormone synthesis from thyroglobulin (TG) occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines and is completed by TG proteolysis3.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [3] Carvalho, D. P. & Dupuy, C. Thyroid hormone biosynthesis and release. Mol. Cell. Endocrinol. 458, 6–15 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The low level of T4 production can be attributed to a lack of flexibility of the backbone near Y171 and Y176, and to their relative orientations, which is different to any of the sites in TG.”
§ The structure of human thyroglobulin > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Clashscore | 4.88”
§ The structure of human thyroglobulin > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A conserved lysine is found in proximity of the donor, and a conserved acidic residue (Glu or Asp) always precedes the acceptor 21.”
§ The structure of human thyroglobulin > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Lamas, L., Anderson, P. C., Foxy, J. W. & Dunn, J. T. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J. Biol. Chem. 264, 13541–13545 (1989). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Identified crosslinked peptide candidates were filtered to an FDR of 2% on residue-pair-level using XiFDR47.”
§ The structure of human thyroglobulin > Methods > Crosslinking and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
Mutating a tyrosine to phenylalanine completely abolishes its ability to act as a hormonogenic donor or acceptor.
“rTG variants where acceptor or donor tyrosines were mutated to phenylalanines, abolishing hormone formation”
The paper relies on this without support.
The four TG hormonogenic sites contribute independently to total T4 production, so their individual activities can be summed.
“the sum of the concentrations measured individually recapitulates the total T4 amount produced by unmodified rTG”
The paper relies on this without support.
The in vitro LPO/TPO iodination assay reproduces the hormonogenic reaction of TG in vivo.
“TH synthesis was performed by rTG in vitro iodination, and the T4 or T3 concentrations were measured by adapting a commercial ELISA assay”
The paper relies on this without support.
TG has 3-4 hormonogenic sites.
“Considering that TG has 3-4 sites, 0.1 μM was determined to be the optimal starting concentration for the assay.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“For the rTG dataset 52 movie frames were recorded, using a fluency of 0.91 electrons per Å2 per frame, for a total accumulated dose of 36.3 electrons per Å2 at a pixel size of 1.149 Å on the specimen.”
§ The structure of human thyroglobulin > Methods > EM sample preparation and data collection
Reported 36.3 · recomputed 47.32
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The structure of human thyroglobulin > Methods > EM sample preparation and data collection
“For the eTG dataset, 40 movie frames were recorded, using a fluency of 1.18 electrons per Å2 per frame, for a total accumulated dose of 47.2 electrons per Å2 at a pixel size of 1.043 Å on the specimen.”
§ The structure of human thyroglobulin > Extended Data
“| Electron exposure (e-/Å2) | 45 | 40 |”
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 46,047
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
SWISS-MODEL: homology modelling of protein structures and complexes
Waterhouse, A. M., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F. T., de Beer, T., Rempfer, C., Bordoli, L., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky427 · Cited by 13,248
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy
Zheng, S. Q., Palovcak, E. J., Armache, J., Verba, K. A., Cheng, Y., & Agard, D. A. (2017) · Nature Methods · doi:10.1038/nmeth.4193 · Cited by 7,496
RELION: Implementation of a Bayesian approach to cryo-EM structure determination
Scheres, S. H. W. (2012) · Journal of Structural Biology · doi:10.1016/j.jsb.2012.09.006 · Cited by 5,446
In-gel digestion for mass spectrometric characterization of proteins and proteomes
Shevchenko, A., Tomas, H., Havli, J., Olsen, J. V., & Mann, M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.468 · Cited by 4,947
New tools for automated high-resolution cryo-EM structure determination in RELION-3
Zivanov, J., Nakane, T., Forsberg, B., Kimanius, D., Hagen, W., Lindahl, E., & Scheres, S. (2018) · eLife · doi:10.7554/elife.42166 · Cited by 4,377
The HHpred interactive server for protein homology detection and structure prediction
Söding, J., Biegert, A., & Lupas, A. N. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki408 · Cited by 3,775
Gctf: Real-time CTF determination and correction
Zhang, K. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.11.003 · Cited by 3,417
Real-space refinement in PHENIX for cryo-EM and crystallography
Afonine, P. V., Poon, B. K., Read, R. J., Sobolev, O. V., Terwilliger, T. C., Urzhumtsev, A., & Adams, P. D. (2018) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s2059798318006551 · Cited by 3,234
Rappsilber, J., Ishihama, Y., & Mann, M. (2002) · Analytical Chemistry · doi:10.1021/ac026117i · Cited by 2,627
Self-citationJPred4: a protein secondary structure prediction server
Drozdetskiy, A., Cole, C., Procter, J. B., & Barton, G. J. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv332 · Cited by 1,714
Global epidemiology of hyperthyroidism and hypothyroidism
Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.18 · Cited by 1,552
A time- and cost-efficient system for high-level protein production in mammalian cells
Aricescu, A. R., Lu, W., & Jones, E. Y. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906029799 · Cited by 770
Thyroid hormone biosynthesis and release
Carvalho, D. P., & Dupuy, C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.038 · Cited by 346
An integrated workflow for crosslinking mass spectrometry
Mendes, M. L., Fischer, L., Chen, Z. A., Barbon, M., O’Reilly, F. J., Giese, S. H., Bohlke‐Schneider, M., Belsom, A., Dau, T., Combe, C., et al. (2019) · Molecular Systems Biology · doi:10.15252/msb.20198994 · Cited by 221
Self-citationChemistry and Biology in the Biosynthesis and Action of Thyroid Hormones
Mondal, S., Raja, K., Schweizer, U., & Mugesh, G. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201601116 · Cited by 220
Gunčar, G., Pungerčič, G., Klemenčič, I., Türk, V., & Turk, D. (1999) · The EMBO Journal · doi:10.1093/emboj/18.4.793 · Cited by 218
Self-citationThe role of thyroglobulin in thyroid hormonogenesis
Citterio, C. E., Targovnik, H. M., & Arvan, P. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0184-8 · Cited by 216
Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology
Di Jeso, B., & Arvan, P. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1090 · Cited by 184
Cryo-EM structure of lysenin pore elucidates membrane insertion by an aerolysin family protein
Bokori‐Brown, M., Martin, T. G., Naylor, C. E., Basak, A. K., Titball, R. W., & Savva, C. G. (2016) · Nature Communications · doi:10.1038/ncomms11293 · Cited by 152
Quirks of Error Estimation in Cross-Linking/Mass Spectrometry
Fischer, L., & Rappsilber, J. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.6b03745 · Cited by 152
Self-citationGnidehou, S., Caillou, B., Talbot, M., Ohayon, R., Kaniewski, J., Noël‐Hudson, M., Morand, S., Agnangji, D., Sezan, A., Courtin, F., et al. (2004) · The FASEB Journal · doi:10.1096/fj.04-2023fje · Cited by 135
Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme
Li, Y., Zhou, M., Hu, Q., Bai, X., Huang, W., Scheres, S. H. W., & Shi, Y. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620626114 · Cited by 135
Consensus Sequences for Early Iodination and Hormonogenesis in Human Thyroglobulin
Lamas, L., Anderson, P. C., Fox, J. W., & Dunn, J. T. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)80031-x · Cited by 112
Molina, F., Bouanani, M., Pau, B., & Granier, C. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.0125h.x · Cited by 106
Thyroid hormone synthesis in thyroglobulin. The mechanism of the coupling reaction.
Gavaret, J. M., Cahnmann, H. J., & Nunez, J. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52523-6 · Cited by 82
MAINsoftware for density averaging, model building, structure refinement and validation
Türk, V. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913008408 · Cited by 82
Effect of Iodide Concentration on Thyroxine Synthesis Catalysed by Thyroid Peroxidase
Pommier, J., Danièle, D. E. M. E., & Nunez, J. (1973) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1973.tb03000.x · Cited by 78
Intrinsic regulation of thyroid function by thyroglobulin
Sellitti, D. F., & Suzuki, K. (2014) · Thyroid® · doi:10.1089/thy.2013.0344 · Cited by 76
Molecular advances in thyroglobulin disorders
Rivolta, C. M., & Targovnik, H. M. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2006.05.043 · Cited by 68
Yang, S.-X., Pollock, H. G., & Rawitch, A. B. (1996) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1996.0093 · Cited by 68
Thyroglobulin Represents a Novel Molecular Architecture of Vertebrates
Holzer, G., Morishita, Y., Fini, J., Lorin, T., Gillet, B., Hughes, S., Tohmé, M., Deléage, G., DEMENEIX, B. A., Arvan, P. R., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719047 · Cited by 57
Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy
Dedieu, A., Gaillard, J.-C., Pourcher, T., Darrouzet, E., & Armengaud, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159483 · Cited by 53
Iodine, Thyroid Autoimmunity and Cancer
Fiore, E., Latrofa, F., & Vitti, P. (2015) · European Thyroid Journal · doi:10.1159/000371741 · Cited by 53
Latrofa, F., Ricci, D., Montanelli, L., Rocchi, R., Piaggi, P., Sisti, E., Grasso, L., Basolo, F., Ugolini, C., Pinchera, A., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2406 · Cited by 52
Favored sites for thyroid hormone formation on the peptide chains of human thyroglobulin.
Dunn, J. T., Kim, P. S., & Dunn, A. D. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)68329-8 · Cited by 51
Spatial requirement for coupling of iodotyrosine residues to form thyroid hormones.
Cahnmann, H. J., Pommier, J., & Nunez, J. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.12.5333 · Cited by 45
Guo, J., McLachlan, S. M., Hutchison, S., & Rapoport, B. (1998) · Endocrinology · doi:10.1210/endo.139.3.5782 · Cited by 41
Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine
Citterio, C. E., Morishita, Y., Dakka, N., Veluswamy, B., & Arvan, P. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001786 · Cited by 34
Selectivity in Tyrosyl Iodination Sites in Human Thyroglobulin
Xiao, S., Dorris, M. L., Rawitch, A. B., & Taurog, A. (1996) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1996.0457 · Cited by 28
Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland
Weber, J., McInnes, J., Kizilirmak, C., Rehders, M., Qatato, M., Wirth, E. K., Schweizer, U., Verrey, F., Heuer, H., & Brix, K. (2017) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2017.02.002 · Cited by 27
Repeat Motif-containing Regions within Thyroglobulin
Lee, J., & Arvan, P. R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.242099 · Cited by 26
Anionic iodotyrosine residues are required for iodothyronine synthesis
de Vijlder, J. J. M., & den Hartog, M. (1998) · European Journal of Endocrinology · doi:10.1530/eje.0.1380227 · Cited by 26
Ledeţi, I., Ledeţi, A., Vlase, G., Vlase, T., Matusz, P. L., Bercean, V. N., Şuta, L.-M., & Piciu, D. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.03.026 · Cited by 24
Sortilin Is a Putative Postendocytic Receptor of Thyroglobulin
Botta, R., Lisi, S., Pinchera, A., Giorgi, F., Marcocci, C., Taddei, A. R., Fausto, A. M., Bernardini, N., Ippolito, C., Mattii, L., et al. (2009) · Endocrinology · doi:10.1210/en.2008-0953 · Cited by 23
THE MOLECULAR WEIGHT OF THYROGLOBULIN
Heidelberger, M. (1934) · Science · doi:10.1126/science.80.2079.414 · Cited by 16
The structure of newly synthesized intracellular thyroglobulin molecules
Berg, G., Björkman, U., & Ekholm, R. (1980) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(80)90096-9 · Cited by 14
An integrated workflow for crosslinking mass spectrometry
Mendes, M. L., Fischer, L., Chen, Z. A., Barbon, M., O’Reilly, F. J., Giese, S., Bohlke-Schneider, M., Belsom, A., Dau, T., Combe, C. W., et al. (2018) · doi:10.1101/355396 · Cited by 11
Self-citationThe Molecular Weight of Thyroglobulin
Heidelberger, M., & Svedberg, T. (1934) · Science · doi:10.1126/science.80.2079.414.a · Cited by 4
Cited by
Sorted by citations
Molecular Mechanisms in Autoimmune Thyroid Disease
Vargas‐Uricoechea, H. (2023) · Cells · doi:10.3390/cells12060918 · Cited by 235
Cellular and molecular basis of thyroid autoimmunity
Bogusławska, J., Godlewska, M., Gajda, E., & Piekiełko-Witkowska, A. (2022) · European Thyroid Journal · doi:10.1530/etj-21-0024 · Cited by 154
Stanojević, M., & Dolenc, M. S. (2025) · Archives of Toxicology · doi:10.1007/s00204-025-04025-z · Cited by 81
The Usefulness of Thyroid Antibodies in the Diagnostic Approach to Autoimmune Thyroid Disease
Vargas‐Uricoechea, H., Nogueira, J. P., Fernández, M. V. P., & Schwarzstein, D. (2023) · Antibodies · doi:10.3390/antib12030048 · Cited by 71
Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61
Metadata
- Authors
- Coscia, F., Taler-Verčič, A., Chang, V. T., Sinn, L., O’Reilly, F. J., Izoré, T., Renko, M., Berger, I., Rappsilber, J., Turk, D., & Löwe, J.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Technische Universität Berlin (DE)
- Jožef Stefan Institute (SI)
- University of Bristol (GB)
- Wellcome Centre for Cell Biology (GB)
- Corresponding author
- Turk, Dušan
- Löwe, Jan
- ORCID
- Venue
- Nature
- Published
- 2020-02-05
- Volume
- 578
- Issue
- 7796
- Pages
- 627-630
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7170718
- OpenAlex
- W3004797639
- Semantic Scholar
- ddcfe1716cc392aaecc3f5bf1709ab4f690dbaa0
- Cited by
- 147
- References
- 49
- Citations by year
- 2026: 21 · 2025: 14 · 2024: 32 · 2023: 29 · 2022: 22 · 2021: 22 · 2020: 7
- FWCI
- 15.01
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Explore Bristol Research (submittedVersion, other-oa)
- Funders
- Wellcome Trust (103139, 103139/Z/13/Z, 202754/Z/16/Z, 202754, 203149)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- thyroglobulin, thyroid hormones, hormone biosynthesis, protein structure, solvent exposure, maltose-binding protein, site-directed mutagenesis
- MeSH terms
- Bacterial Proteins, Humans, Models, Molecular, Mutation, Solvents, Thyroglobulin, Thyroid Hormones, Tyrosine, Reproducibility of Results, Cryoelectron Microscopy, HEK293 Cells, Maltose-Binding Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-03, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-03 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
