The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index; 11 of the 31 sources its claims cite were checked for support.
ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2
Open accessAbstract
Mutations in the phosphotyrosine binding domain protein ARH cause autosomal recessive hypercholesterolemia, a disorder caused by defective internalization of low density lipoprotein receptors (LDLR) in the liver. To examine the function of ARH, we used pull-down experiments to test for interactions between ARH, the LDLR, and proteins involved in clathrin-mediated endocytosis. The phosphotyrosine binding domain of ARH interacted with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR in a sequence-specific manner. Mutations in the NPVY sequence that were previously shown to decrease LDLR internalization abolished in vitro binding to ARH. Recombinant ARH bound purified bovine clathrin with high affinity (K(D), approximately 44 nm). The interaction between ARH and clathrin was mapped to a canonical clathrin box sequence (LLDLE) in ARH and to the N-terminal domain of the clathrin heavy chain. A highly conserved 20-amino acid sequence in the C-terminal region of ARH bound the beta(2)-adaptin subunit of AP-2. Mutation of a glutamic acid residue in the appendage domain of beta(2)-adaptin that is required for interaction with the adapter protein beta-arrestin markedly reduced binding to ARH. These data are consistent with the hypothesis that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.
Overview
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Written from the paper’s full text.
TL;DR
ARH, the protein mutated in autosomal recessive hypercholesterolemia, binds the LDL receptor cytoplasmic tail, clathrin, and the β2-adaptin subunit of AP-2 through distinct conserved motifs, supporting its proposed role as a modular adaptor that couples LDLR to the endocytic machinery. All interactions were demonstrated in vitro with recombinant proteins.
Key findings
- The ARH PTB domain binds the LDLR cytoplasmic tail in a sequence-specific manner: full-length ARH and ARH(1–219) bound the tail, whereas ARH(188–308) lacking the PTB domain did not. Mutating LDLR Tyr-807 to cysteine or alanine (substitutions previously shown to abolish LDLR internalization) markedly reduced binding, while Y807F had no effect, indicating an aromatic residue at position 807 is required and phosphorylation is not.
- Mutation of ARH Phe-165 to valine or alanine abolished binding to the LDLR tail, consistent with a model based on the X11 PTB domain structure.
- Recombinant ARH bound purified bovine clathrin with high affinity (K_D ∼44 nM). Binding mapped to the clathrin box motif LLDLE (residues 212–216) and to the N-terminal domain of the clathrin heavy chain (residues 1–494); replacing the first two leucines or the two acidic residues with alanines abolished binding.
- ARH bound the β2-adaptin appendage domain (residues 664–937) but not the N-terminal 587 residues. β2-adaptin E849A abolished binding, E902A reduced but did not abolish it; on ARH, residues 260–279 were required, and R266A completely abolished binding while R261 mutation had little effect.
- ARH sequences are conserved across species: mouse, frog, and zebrafish ARH share 89%, 72%, and 61% identity with human ARH, respectively, with 54% of amino acids identical in all four; four conserved regions were identified (N-terminal 44 aa, PTB domain residues 45–175, clathrin box 212–216, and residues 249–276).
Methods
- In vitro pull-down assays: recombinant His-tagged full-length and truncated/mutated ARH proteins (expressed in *E. coli* BL21(DE3), purified on Ni-NTA) incubated with GST fusion proteins (LDLR cytoplasmic tail, clathrin N-terminal domain 1–494, β2-adaptin fragments and mutants), followed by SDS-PAGE and immunoblotting with anti-His6, anti-GST, anti-clathrin, or anti-LDLR antibodies.
- Clathrin binding assays: His6·ARH immobilized on Ni-NTA beads incubated with 125I-Bolton-Hunter-labeled clathrin purified from bovine brain; bound/free separation through a sucrose cushion; assays in triplicate with nonspecific binding subtracted; Scatchard analysis for affinity.
- Phylogenetic analysis: mouse, frog (*Xenopus laevis*), and zebrafish ARH orthologs cloned by RT-PCR from liver, oocyte, and embryo mRNA using EST sequences; alignment with ClustalW. Site-directed mutagenesis via QuikChange; all constructs verified by DNA sequencing.
Limitations
- Stated by the authors: because binding studies used recombinant proteins in vitro, they do not constitute direct evidence that ARH interacts with LDLR, clathrin, and β2-adaptin in vivo, nor that these interactions are required for ARH function; further studies are needed to confirm this.
- Stated by the authors: elucidation of ARH's specific role has been hampered by the lack of an ARH-deficient cell line with significantly impaired LDLR function, and LDL uptake in ARH-patient fibroblasts is normal or only moderately impaired; it is not known why ARH is required in hepatocytes but not fibroblasts.
- Evident from the text: the PTB–LDLR interaction model is based on homology modeling to the X11 crystal structure rather than a structure of ARH itself, and the proposed correspondence of ARH Arg-266 to arrestin arginines interacting with β2-adaptin Glu-849 is presented as a possibility ("may interact") rather than demonstrated.
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Claims the paper makes
11 of 31 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“This finding indicates that LDLR function is markedly impaired in the hepatocytes of ARH patients.”
What the sources say
- Could not verifycites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. sourceExperimental — accuracy not yet measured
The indexed passages contain a bibliographic record and keywords under an Abstract label, but no substantive passage about LDLR function in hepatocytes. Searches for hepatocyte LDLR impairment, hepatic receptor activity, and LDL turnover returned only that record, so our copy does not establish the attributed claim. (LLM, conf=0.76)
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Immortalized lymphoblasts from ARH patients have more LDLRs on the plasma membrane; however, despite increased cell surface binding of LDL, LDL degradation is decreased by ∼75% compared with lymphoblasts from normal individuals (5”
What the sources say
- Supportedcites [5] Norman, 1999, J. Clin. Invest. source
The Analysis of LDL receptor function reports that all LDL receptor protein in the two patients’ lymphoblasts was accessible at the cell surface, compared with approximately 60% in normal cells. The Discussion likewise states that essentially all receptor protein in patient cells was on the surface, whereas about half was inside normal cells. No page numbers are available in our copy. (LLM, conf=0.91)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“a disorder caused by defective internalization of low density lipoprotein receptors (LDLR) in the liver.”
What the sources say
- Could not verifycites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. sourceExperimental — accuracy not yet measured
The indexed copy shows the paper’s title and, in a repository entry labelled Abstract, keywords including “LDL receptor” and “LDL turnover.” It contains no passage about defective LDL-receptor internalization in the liver. Searches for that mechanism and for hepatic LDL uptake returned only repository metadata, so the claim cannot be verified from this copy. (LLM, conf=0.73)
- Partly supportedcites [5] Norman, 1999, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The Discussion describes two patients whose disorder appears to be inherited as an autosomal recessive trait, and the Analysis of LDL receptor function reports that their receptors bind LDL but are not internalized. The experiments used cultured patient cells, not liver cells, so the paper does not establish the claim’s liver-specific mechanism. (LLM, conf=0.87)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“In contrast, LDLR function is normal or only moderately reduced in fibroblasts from patients with this disorder (3”
What the sources say
- Could not verifycites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. sourceExperimental — accuracy not yet measured
An unlabeled passage (page unavailable) describes reduced LDL uptake in the liver and proposes a selective hepatic LDL-receptor defect. The supplied passages and searches for fibroblast LDL-receptor activity do not address whether function in patients’ fibroblasts is normal or moderately reduced. (LLM, conf=0.70)
- Not checked — no full text of the sourcecites [4] Arca, 2002, Lancet source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“studies using plasmon resonance to test for direct interactions between AP-2 and the FXNPXY motif of the LDLR tail have yielded contradictory results (13”
What the sources say
- Partly supportedcites [13] Boll, 1996, EMBO J. sourceExperimental — accuracy not yet measured
The Abstract (page not specified) says the paper used surface plasmon resonance to study AP-2 interactions with tyrosine-based Yppø signals. It does not report tests of the LDLR tail’s FXNPXY motif or contradictory results; the Selected References (p. 5790) mention the LDL receptor’s NPXY signal but do not establish those claims. (LLM, conf=0.80)
- Not checked — no full text of the sourcecites [14] Boll, 2002, Traffic source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Modeling of the ARH PTB domain based on the X11 crystal structure suggests that the FDNPVY sequence of the LDLR cytoplasmic tail interacts as an extension of the β-sheet of the ARH PTB domain.”
What the sources say
- Supportedcites [19] Zhang, 1997, EMBO J. source
The Abstract (page unavailable) reports that the crystal structure of the X11 PTB domain was determined. The cited paper therefore supports its identification as the structural basis for the citing authors’ ARH model; the ARH prediction is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.87)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The ARH PTB domain adopts a fold sufficiently similar to the X11 PTB domain that the X11 crystal structure can be used to model how the ARH PTB domain binds the FDNPVY sequence.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Recently, LDL degradation was shown to be markedly reduced in transformed lymphocytes from ARH patients (5”
What the sources say
- Supportedcites [5] Norman, 1999, J. Clin. Invest. source
The ‘Analysis of LDL receptor function’ section states that neither index-patient cell line could degrade labeled LDL (Figure 3). The paper identifies the patients’ cells as EBV-transformed lymphoblasts in ‘Analysis of the LDL receptor protein,’ supporting the claim about transformed lymphocytes. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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 proteins that included residues 260–279 bound β2-adaptin.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Substitution of both the aspartic acid and glutamic acid residues with alanines also abolished binding.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 mutation of Phe-165 in ARH to either valine or alanine produced a protein that failed to bind the LDLR cytoplasmic tail (Fig. 2 C).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 19
- Probably not a substantial claim. 8
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Immortalized lymphoblasts from ARH patients have more LDLRs on the plasma membrane; however, despite increased cell surface binding of LDL, LDL degradation is decreased by ∼75% compared with lymphoblasts from normal individuals (5”
What the sources say
- Partly supportedcites [5] Norman, 1999, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The Analysis of LDL receptor function (page unavailable) reports that the patients’ lymphoblasts had LDL receptors on the cell surface, bound at least as much LDL as normal cells, and were unable to degrade labeled LDL. It does not report an approximately 75% decrease or establish that LDL binding was increased rather than equal. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
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
“The adaptor protein AP-2 has been shown to bind other receptors that are internalized via clathrin-coated pits”
What the sources say
- Supportedcites [13] Boll, 1996, EMBO J. source
The Abstract in our indexed copy states that AP-2 interacts with several endocytic signal sequences found on receptors that follow the clathrin pathway. It also identifies AP-2 as a complex involved in clathrin coat formation and endocytosis, supporting the citing sentence’s paraphrase. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [14] Boll, 2002, Traffic source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Peptides containing the sequence FDNPVY will bind the terminal domain of clathrin in vitro (15”
What the sources say
- Supportedcites [15] Kibbey, 1998, J. Cell Biol. source
The Results report that the wild-type FDNPVY hexapeptide interacted with a purified recombinant clathrin terminal domain in a line-broadening assay. The Discussion likewise states that the wild-type peptide interacted with the terminal domain but not the hub portion of clathrin. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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
“Mutation of Arg-261 did not significantly affect binding to β2-adaptin, whereas mutation of Arg-266 to alanine completely abolished binding.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Truncation of the ARH protein before the clathrin box (residue 212) or replacement of the first two leucine residues of the clathrin box with alanine residues abolished binding to clathrin.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“GST pull-down experiments indicated that ARH can interact with the appendage domain of β2-adaptin and that this interaction requires one of the glutamic acid residues (Glu-849) in β2-adaptin that mediate binding to β-arrestin.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Mutation of residue Glu-849 in β2-adaptin to alanine abolished binding to ARH, whereas mutation of residue Glu-902 reduced but did not abolish binding.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 mouse, frog, and zebrafish genomes encode proteins that share 89, 72, and 61% sequence identity with human ARH, respectively (Fig.1).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“ARH bound residues 664–937 of β2-adaptin but not to a fragment containing the N-terminal 587 residues of the protein.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 major finding of this paper is that ARH binds to the LDLR cytoplasmic tail as well as to two components of the clathrin-coated pit, the heavy chain of clathrin, and the β2-adaptin subunit of the adaptor protein AP-2.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Substitution of the tyrosine in the NPVY motif (Tyr-807) with alanine or cysteine markedly reduced the interaction between ARH and the LDLR tail, whereas the introduction of phenylalanine at this position did not alter the interaction between the two proteins.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Four major regions of sequence conservation were identified: the N-terminal 44 amino acids, the PTB domain (residues 45 to 175), a 5-amino acid sequence similar to the clathrin box motif (LLDLE, residues 212–216) of other proteins (18”
What the sources say
- Not checked — no full text of the sourcecites [18] Dell'Angelica, 2001, Trends Cell Biol. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Full-length ARH and a fragment containing the PTB domain (residues 1–219) bound the LDLR tail (Fig.2 A).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 region of ARH that is required for binding to β2-adaptin is distinct from the LDLR and clathrin binding domains and is highly conserved among human, mouse, frog, and zebrafish.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The PTB domains of adaptor proteins such as SHC, IRS-1, X11, Dab-1, and Dab-2 bind a canonical sequence motif (NPXY) in the cytoplasmic tails of various cell surface receptors (8”
- Also stated in: § RESULTS · plain
“PTB domains in several proteins, including SHC, IRS2, and Dab-1, bind receptor tails containing the motif NPXY (8”
What the sources say
- Not checked — no full text of the sourcecites [8] Forman-Kay, 1999, Curr. Opin. Struct. Biol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Also stated in: § RESULTS · plain
In the paper
“Reductions in hepatic LDLR activity result in elevated plasma LDL-cholesterol concentrations and the deposition of cholesterol in body tissues (1”
What the sources say
- Not matchedcites [1] Goldstein, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“PTB domains are found in several adaptor proteins that link proteins into functional complexes to orchestrate transmembrane signaling and endocytosis (7”
What the sources say
- Not checked — no full text of the sourcecites [7] Guy, 2002, Cell. Signal. source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In fibroblasts, LDLRs cluster on the cell surface in clathrin-coated pits that invaginate and detach from the plasma membrane as coated vesicles (1”
What the sources say
- Not matchedcites [1] Goldstein, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“LDL receptor (LDLR)-mediated endocytosis in the liver is the primary pathway for the clearance of circulating LDL (1”
What the sources say
- Not matchedcites [1] Goldstein, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“A naturally occurring mutation that changes the tyrosine of the NPVY motif to cysteine (Y807C) prevents LDLRs from clustering; receptors in cells from this patient are distributed diffusely over the cell surface (11”
What the sources say
- Not checked — no full text of the sourcecites [11] Davis, 1986, Cell source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Our data indicate that evolutionarily conserved motifs in ARH mediate direct interactions between ARH and the LDLR, ARH and the terminal domain of the clathrin heavy chain, and ARH and the β2-adaptin subunit of AP-2.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“These findings suggest that the NPVY sequence plays a conformational role that is critical for endocytosis of the LDLR, presumably by mediating binding to adaptor proteins.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“LDL uptake in fibroblasts from ARH patients is normal or only moderately impaired (4”
What the sources say
- Not checked — no full text of the sourcecites [4] Arca, 2002, Lancet source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“because the binding studies were performed with recombinant proteins in vitro, they do not constitute direct evidence that ARH interacts with the LDLR, clathrin, and β2-adaptin in vivo or that interaction with these proteins is important for ARH function.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“that mediates binding of various proteins to the terminal domain of the clathrin heavy chain (18”
What the sources say
- Not checked — no full text of the sourcecites [18] Dell'Angelica, 2001, Trends Cell Biol. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The identities of the proteins that bind the FDNPVY sequence in the LDLR tail are not known.
“The identities of the proteins that bind the FDNPVY sequence in the LDLR tail are not known.”
The paper relies on this without support.
It is not known whether the interaction between FDNPVY-containing peptides and the clathrin terminal domain is sufficient to mediate internalization of the LDLR.
“but it is not known if this interaction is sufficient to mediate internalization of the receptor.”
The paper relies on this without support.
The in vitro interactions of recombinant ARH with LDLR, clathrin, and AP-2 reflect the interactions that mediate LDLR endocytosis in vivo.
“These data are consistent with the hypothesis that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.”
The paper relies on this without support.
The ARH PTB domain adopts a fold sufficiently similar to the X11 PTB domain that the X11 crystal structure can be used to model how the ARH PTB domain binds the FDNPVY sequence.
“Modeling of the ARH PTB domain based on the X11 crystal structure suggests that the FDNPVY sequence of the LDLR cytoplasmic tail interacts as an extension of the β-sheet of the ARH PTB domain.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“which encodes a putative adaptor protein that interacts with the cytoplasmic tail of the LDLR, phospholipids, and two components of the clathrin endocytic machinery, clathrin and adaptor protein-2 (AP-2) in vitro.”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Following the clathrin box motif, the protein has a highly conserved amino acid sequence (residues 252-268) that binds the 2-adaptin subunit of the adaptor protein-2 (AP-2) (13,15).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Amino acids 44 -178 encode a phosphotyrosine binding (PTB) domain that binds the internalization sequence (FDNPVY) in the LDLR cytoplasmic tail (11,13) and phosphoinositides (11).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Therefore, the majority of studies so far available have been carried out on lymphocytes from ARH patients, in which the LDLR function is significantly impaired (13,14).”
From Adaptor Protein ARH Is Recruited to the Plasma Membrane by Low Density Lipoprotein (LDL) Binding and Modulates Endocytosis of the LDL/LDL Receptor Complex in Hepatocytes (2005) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Their cytosolic tails interact via the FLVHRY motif of sortilin with the YNPTYKFFE motif in APP, which overlaps with the ARH binding consensus YENPTY (26,27).”
From Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other (2015) · cites this paper as [27]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“In vitro studies with purified recombinant proteins indicate that the PTB domain of ARH binds to the unphosphorylated FDNPVY internalization sequence in LDLR in a sequence-specific manner (8,9).”
The cited source says what the claim attributes to it.
In the citing paper
“Finally ARH contains a highly conserved sequence at its C terminus that binds the  2 -subunit of AP2, a second structural protein in coated pits (9).”
The cited source says what the claim attributes to it.
In the citing paper
“The clathrin box sequence in ARH can mediate high affinity binding to the heavy chain of clathrin (8,9).”
The cited source says what the claim attributes to it.
In the citing paper
“Data from in vitro pull-down experiments are consistent with the hypothesis that ARH functions as an endocytic adaptor that links the LDLR to structural components of the coated pit (11,13).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“In vitro pulldown studies defined sequences within ARH that interact with the LDLR, the terminal domain of the heavy chain of clathrin, and 2-adaptin, a component of AP-2 (11, 13).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“A similar result was obtained (Fig. 8B) when we substituted alanine for arginine at position 266 (AdARH-R266A) to abolish interactions between ARH and AP-2 (13).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Residues 212-216 comprise a canonical clathrin box sequence (LLDLE) that mediates high affinity binding to the terminal domain of the heavy chain of clathrin (11,13,14).”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Substitution of the tyrosine in the FDNPVY motif (Tyr 807 ) with alanine, which markedly reduced the interaction between ARH and the LDLR tail in vitro (11,13), also resulted in a failure of ARH to promote clustering of LDLRs in the WIF-B cells.”
From The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits (2005) · cites this paper as [13]
In the citing paper
“It has been demonstrated that ARH is required for the efficient internalization of the LDL-LDLR complex and to stabilize the association of the receptor with LDL in Epstein-Barr virus-immortalized B lymphocytes.”
In the citing paper
“As already reported in the literature (14), we observed co-immunoprecipitation of the ARH protein with several components of the plasma membrane endocytic system, including the  subunit of the AP-2 complex (-adaptin) and the Dab2 protein.”
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.
β2-adaptin fragment has conflicting endpoint
MinorThe methods list a β2-adaptin construct spanning residues 1-538, but the results describe the tested N-terminal fragment as containing 587 residues.
“Plasmids containing fragments of the human β2-adaptin subunit of AP-2 fused to GST (GST·AP21–538, GST·AP2 664–937, GST·AP2 E849A, and GST·AP2 E902A) were obtained from Dr. Marc Caron (Duke University).”
“ARH bound residues 664–937 of β2-adaptin but not to a fragment containing the N-terminal 587 residues of the protein.”
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Metadata
- Authors
- He, G., Gupta, S., Yi, M., Michaely, P., Hobbs, H. H., & Cohen, J. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cohen, Jonathan C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 277
- Issue
- 46
- Pages
- 44044-44049
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2020331445
- Cited by
- 232
- References
- 31
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 3 · 2023: 4 · 2022: 11 · 2021: 5 · 2020: 9 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 12 · 2014: 15 · 2013: 11 · 2012: 11
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL053917, P01HL020948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- ArH+, adaptor proteins, LDL receptor, clathrin, AP-2, clathrin-mediated endocytosis, phosphotyrosine binding domain, autosomal recessive hypercholesterolemia, beta-arrestin, liver
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Carrier Proteins, Clathrin, Endocytosis, Glutathione Transferase, Humans, Hyperlipoproteinemia Type II, Models, Molecular, Molecular Sequence Data, Mutation, Plasmids, Protein Binding, Receptors, LDL, Recombinant Fusion Proteins, Recombinant Proteins, Xenopus, Zebrafish, Immunoblotting, Protein Structure, Tertiary, Glutamic Acid, Adaptor Proteins, Vesicular Transport, Adaptor Protein Complex 2, Adaptor Protein Complex beta Subunits, Adaptor Proteins, Signal Transducing, Mice
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.
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