The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index; 20 of the 40 sources its claims cite were checked for support.
The Modular Adaptor Protein Autosomal Recessive Hypercholesterolemia (ARH) Promotes Low Density Lipoprotein Receptor Clustering into Clathrin-coated Pits
Open accessAbstract
Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis. LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with this disorder. The disease is caused by mutations in ARH, 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. To determine the physiological relevance of these interactions, we examined the effect of mutations in the ARH on LDLR location and function in polarized hepatocytes (WIF-B). The integrity of the FDNPVY sequence in the LDLR cytoplasmic tail was required for ARH-associated LDLR clustering into clathrin-coated pits. The phosphotyrosine binding domain of ARH plus either the clathrin box or the AP-2 binding region were required for both clustering and internalization of the LDLR. Parallel studies performed in vivo with the same recombinant forms of ARH in livers of Arh(-/-) mice confirmed the relevance of the cell culture findings. These results demonstrate that ARH must bind the LDLR tail and either clathrin or AP-2 to promote receptor clustering and internalization of LDL.
Overview
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Written from the paper’s full text.
TL;DR
ARH promotes clustering of the LDLR into clathrin-coated pits in polarized hepatocytes and is required for efficient LDLR internalization and hepatic LDL clearance. The LDLR FDNPVY motif and ARH’s PTB domain plus either its clathrin box or AP-2 binding region are required for clustering and internalization.
Key findings
- In WIF-B hepatocytes, co-expression of ARH with LDLR caused LDLR clustering into clathrin-coated pits; immunogold quantification in Table One showed LDLR alone at 1.78 gold particles/µm on non-coated pit membrane versus 0.43 on coated pit membrane, while LDLR+ARH showed 0.10 versus 3.36. The text describes a ~33-fold increase in LDLRs/µm of coated pit membrane and a ~9-fold reduction in LDLRs per µm of plasma membrane.
- ARH-mediated clustering and internalization required the LDLR cytoplasmic FDNPVY sequence: ARH clustered wild-type LDLR but not LDLR-Y807A, and LDLR-Y807A plus ARH failed to internalize.
- ARH required an intact PTB domain plus either the clathrin box or the AP-2 binding region: ARH-S117Y and ARH-N187X failed to promote clustering; single clathrin-box (L212A/L213A) or AP-2 (R266A) mutants supported clustering, but the double mutant LL/AA/R266A did not.
- In Arh−/− mice fed a high fat/high cholesterol diet, plasma cholesterol rose 4–7-fold to 375–700 mg/dl; wild-type ARH expression reduced circulating cholesterol by 50%, whereas PTB mutants F165A or S117Y failed to lower LDL-C and clathrin-box or AP-2 single mutants lowered cholesterol similarly to wild-type, while the double mutant did not.
Methods
- Polarized WIF-B cells (rat hepatocyte–human fibroblast fusion) were infected with recombinant adenoviruses expressing human LDLR (wild-type or Y807A) and wild-type or mutant ARH; LDLR localization was assessed by immunofluorescence confocal microscopy, immunoelectron microscopy with gold-labeled LDLR or LDL, and receptor internalization assays using IgG-C7.
- In vivo, Arh−/− mice on a C57Bl/6 and 126sv hybrid background were fed a 2% cholesterol, 21% anhydrous milk fat diet for 3–5 weeks, then injected with recombinant adenovirus (2 × 10^11 pfu) expressing wild-type or mutant ARH; plasma cholesterol was measured before and 4 days after injection.
- Main analyses included immunoblotting for LDLR and ARH expression, enzymatic plasma cholesterol measurement, and quantification of immunogold particles per micrometer of non-coated versus coated pit membrane.
Limitations
- The authors state that the static morphological techniques used could not define the temporal sequence of interactions between ARH, LDLR, and proteins/lipids in coated pits.
- The authors state they could not determine whether ARH-mediated increases in LDLR internalization are simply a consequence of increased receptor clustering or whether ARH also directly affects internalization once the receptor reaches coated pits, because no mutation uncouples clustering from internalization.
- The authors note that endogenous ARH in WIF-B cells failed to promote clustering of recombinant LDLRs, possibly because expression was too low or because of species differences between endogenous ARH and recombinant human LDLR; they also speculate that high ARH-F165A expression may compensate for reduced LDLR-tail affinity in WIF-B cells, since F165A supported clustering in vitro but failed to rescue ARH activity in mice.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
20 of 40 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in LDLR endocytosis.
“Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis.”
- Also stated in: § Abstract · plain
“however, unlike FH, the defect in LDLR endocytosis is cell type-specific.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
The available indexed passages are repository metadata: the title identifies familial recessive hypercholesterolemia, and the passage labeled Abstract lists “LDL receptor” and “LDL turnover” only as keywords. Searches for cell-type specificity, LDLR endocytosis, and internalization found no passage addressing the claimed defect; the listed PDF's contents are not present in the passages. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [8] Zuliani, 1995, Eur. J. Clin. Investig. source
- Also stated in: § Abstract · plain
- Premisecitation
In ARH-deficient lymphocytes, LDLRs accumulate on the plasma membrane, primarily outside of coated pits.
“In ARH-deficient lymphocytes, LDLRs accumulate on the plasma membrane, primarily outside of coated pits (10)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Michaely, 2004, J. Biol. Chem. source
- Premisecitation
Residues 212-216 of ARH comprise a clathrin box sequence (LLDLE) that mediates high affinity binding to the terminal domain of the heavy chain of clathrin.
“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).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
Data from in vitro pull-down experiments are consistent with ARH functioning as an endocytic adaptor that links the LDLR to structural components of the coated pit.
“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).”
Quote in the paperSubstantial claim1 of 2 sources checked - Interpretationcitation
ARH is required for the normal transit of LDLR from the cell surface to endosomes.
“These observations indicate that ARH is required for the normal transit of LDLR from the cell surface to endosomes.”
Quote in the paperSubstantial claim2 of 2 sources checked
- Premisecitation
In vitro pulldown studies defined sequences within ARH that interact with the LDLR, the terminal domain of the heavy chain of clathrin, and β2-adaptin.
“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).”
Quote in the paperSubstantial claim1 of 2 sources checked - Findingown data
The AP-2 binding mutant ARH-R266A supports clustering of LDLR in WIF-B cells.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] He, 2002, J. Biol. Chem. source
- Findingown data
Substitution of the tyrosine in the FDNPVY motif (Tyr807) with alanine resulted in a failure of ARH to promote clustering of LDLRs in WIF-B cells.
“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.”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
The density of LDLRs in coated pit membranes is similar in normal and in ARH-deficient lymphocytes.
“the density of LDLRs in coated pit membranes is similar in normal and in ARH-deficient lymphocytes (10).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [10] Michaely, 2004, J. Biol. Chem. source
- Premisecitation
The vast majority of LDLRs in lymphocytes are located in intracellular, EEA1-positive vesicles.
“In contrast the vast majority of LDLRs in lymphocytes are located in intracellular, EEA1-positive vesicles (10 -12).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] Michaely, 2004, J. Biol. Chem. source
The Results (Fig. 2) report that LDLR staining in normal lymphocytes was predominantly internal and co-localized with EEA1. The claim omits the normal-cell qualifier: in ARH-deficient lymphocytes, the paper instead found LDLR predominantly on the cell surface. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [11] Mishra, 2002, Proc. Natl. Acad. Sci. U. S. A. source
- cites [12] Eden, 2002, J. Clin. Investig. source
In “Expression of exogenous ARH1 in mutant EBV-lymphocytes” (page not specified), LDL receptors appeared as intracellular puncta in control cells after incubation at 37°C. The paper does not identify those puncta as EEA1-positive or say that the vast majority of receptors are intracellular; it reports surface staining at 4°C and continued surface staining in ARH1-negative cells at 37°C. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Residues 252-268 of ARH bind the β2-adaptin subunit of AP-2.
“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).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [13] He, 2002, J. Biol. Chem. source
The binding experiments in our copy (labeled Abstract; no page given) show that ARH interacts with β2-adaptin and identify a conserved binding region. They locate that region at residues 260–279, not 252–268, so the cited source does not support the claimed residue boundaries. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [15] Mishra, 2005, J. Biol. Chem. source
- Findingown data
The PTB domain of ARH plus either the clathrin box or the AP-2 binding region are required for both clustering and internalization of the LDLR.
“The phosphotyrosine binding domain of ARH plus either the clathrin box or the AP-2 binding region were required for both clustering and internalization of the LDLR.”
Quote in the paperSubstantial claim - Findingown data
The integrity of the FDNPVY sequence in the LDLR cytoplasmic tail is required for ARH-associated LDLR clustering into clathrin-coated pits.
“The integrity of the FDNPVY sequence in the LDLR cytoplasmic tail was required for ARH-associated LDLR clustering into clathrin-coated pits.”
- Also stated in: § Expression of Recombinant ARH Results in Cell Surface · plain
“Thus, the ability of ARH to drive LDLR clustering in the WIF-B cells required the integrity of the FDNPVY internalization sequence in the LDLR cytoplasmic tail.”
Quote in the paperSubstantial claim - Also stated in: § Expression of Recombinant ARH Results in Cell Surface · plain
- Findingnone given
ARH expression from the recombinant adenovirus was sufficient to restore LDLR endocytosis in the Arh-/- mice without addition of doxycycline.
“Because ARH expression from the recombinant adenovirus was sufficient to restore LDLR endocytosis in the Arh Ϫ/Ϫ mice without addition of doxycycline, no doxycycline was supplied to the mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenoviral-mediated hepatic expression of ARH in Arh-/- mice reconstitutes ARH function in a physiologically relevant manner.
- Findingown data
Disruption of either the clathrin box or the AP-2 binding sites alone did not prevent association of the LDLR with coated pits.
“Disruption of either the clathrin box or the AP-2 binding sites alone did not prevent association of the LDLR with coated pits.”
Quote in the paperSubstantial claim - Findingown data
In vivo studies with the same recombinant forms of ARH in livers of Arh-/- mice confirmed the relevance of the cell culture findings.
“Parallel studies performed in vivo with the same recombinant forms of ARH in livers of Arh ؊/؊ mice confirmed the relevance of the cell culture findings.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of recombinant human ARH in WIF-B cells does not change the distribution of AP-2 or clathrin.
“we did not observe changes in the distribution of AP-2 or clathrin with the overexpression of recombinant human ARH in WIF-B cells (AdARH) (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
In cells expressing wild-type LDLR, almost all receptors remain on the cell surface.
“In cells expressing wild-type LDLR, almost all the receptors remained on the cell surface (Fig. 9).”
Quote in the paperSubstantial claim - Findingown data
Expression of ARH-F165A in WIF-B cells is associated with clustering of LDLR.
“Expression of ARH-F165A in WIF-B cells was associated with clustering of LDLR (Fig. 8B).”
Quote in the paperSubstantial claim - Findingown data
In cells co-expressing ARH and LDLR, LDL-gold is found predominantly inside the cells.
“The LDL-gold was found predominantly inside the cells co-expressing ARH and LDLR (Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data
In WIF-B cells expressing LDLR alone, gold-labeled LDLR density was higher on non-coated pit membrane (1.78 gold/μm) than on coated pit membrane (0.43 gold/μm).
“LDLR 25 634 1128 1.78 14 6 0.43”
Quote in the paperSubstantial claim- Rests on an assumption: Immunogold labeling density on EM sections quantitatively reflects the surface distribution of LDLR.
- Findingown data
Feeding Arh-/- mice a high fat-high cholesterol diet (2% cholesterol, 21% milk fat) for 3-5 weeks resulted in a 4-7-fold increase in plasma cholesterol (375-700 mg/dl).
“the mice were fed a high fat-high cholesterol diet (2% cholesterol, 21% milk fat) for 3-5 weeks, resulting in a 4 -7-fold increase in plasma cholesterol (375-700 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
The ARH-induced changes in the cellular distribution of LDLR required either (but not both) a clathrin box or an AP-2 binding motif in ARH.
“and an intact PTB domain together with either (but not both) a clathrin box or an AP-2 binding motif in ARH.”
Quote in the paperSubstantial claim - Findingown data
No reduction in cholesterol level was seen in Arh-/- mice expressing ARH containing both mutations (AdARH-LL/AA/R266A).
“no reduction in cholesterol level was seen in association with expression of the recombinant adenovirus expressing an ARH containing both mutations (AdARH-LL/AA/R266A)”
Quote in the paperSubstantial claim - Findingown data
When ARH and LDLR were co-expressed in WIF-B cells, the LDLR clustered in coated pits.
“When ARH and LDLR were co-expressed in these cells, the LDLR clustered in coated pits.”
Quote in the paperSubstantial claim - Findingown data
The majority of ARH staining on the plasma membrane of WIF-B cells co-localizes with AP-2 and clathrin-HC.
“The majority of ARH staining on the plasma membrane colocalized with AP-2 and clathrin-HC”
Quote in the paperSubstantial claim - Findingown data
Expression of a control adenovirus in these mice produced no significant change in plasma cholesterol levels.
“whereas no significant change in cholesterol levels occurred in mice expressing a control adenovirus (Fig. 10, A and B).”
Quote in the paperSubstantial claim - Findingown data
Recombinant ARH constructs containing either the ARH-F165A or ARH-S117Y mutation in the PTB domain failed to lower LDL-C levels in Arh-/- mice.
“Expression of recombinant ARH constructs containing either the ARH-F165A or the ARH-S117Y mutations in the PTB domain failed to lower LDL-C levels”
Quote in the paperSubstantial claim- Rests on an assumption: The ARH mutations used (F165A, S117Y, L212A/L213A, R266A, LL/AA/R266A) affect only the intended binding interactions and not overall protein folding or stability.
- Findingown data
ARH-F165A supported receptor clustering in WIF-B cells.
“ARH-F165A supported receptor clustering in WIF-B cells”
Quote in the paperSubstantial claim - Findingown data
Expression of ARH-S117Y in WIF-B cells does not result in clustering of LDLRs.
“Expression of ARH-S117Y in WIF-B cells did not result in clustering of the LDLRs (Fig. 8B).”
Quote in the paperSubstantial claim - Findingown data
The ARH-induced changes in the cellular distribution of LDLR required an intact PTB domain in ARH.
“and an intact PTB domain together with either (but not both) a clathrin box or an AP-2 binding motif in ARH.”
Quote in the paperSubstantial claim - Findingown data
Co-expression of ARH with LDLR in WIF-B cells results in punctate LDLR staining.
“co-expression of ARH with LDLR resulted in punctate staining”
Quote in the paperSubstantial claim - Findingown data
Only coexpression of ARH with LDLR in WIF-B cells resulted in clustering of receptors into coated pits.
“Only coexpression of ARH with LDLR in the WIF-B cells resulted in clustering of receptors into coated pits, as observed by electron microscopy (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of ARH alone does not change the cell surface or intracellular distribution of endogenous LDLR in WIF-B cells.
“No changes in the cell surface or intracellular distribution of the LDLR were seen (data not shown).”
Quote in the paperSubstantial claim - Findingown data
The clathrin box mutant ARH-L212A/L213A supports clustering of LDLR in WIF-B cells.
“Unlike the truncated ARH construct (ARH-N187X), the clathrin box mutant supported clustering of the LDLR in the WIF-B cells (Fig. 8B).”
Quote in the paperSubstantial claim - Findingown data
In WIF-B cells co-expressing ARH, a large fraction of the LDLR is intracellular.
“whereas in cells co-expressing ARH, a large fraction of the LDLR was intracellular (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
In WIF-B cells co-expressing LDLR and ARH, immunogold particles cluster into coated pits.
“the immunogold particles clustered into coated pits, in cells co-expressing LDLR and ARH.”
Quote in the paperSubstantial claim - Findingown data
Expression of a truncated form of ARH (ARH-N187X) fails to promote LDLR clustering.
“The expression of a truncated form of ARH (ARH-N187X), containing the PTB domain but not the clathrin box or the AP-2 binding region, failed to promote LDLR clustering (Fig. 8B).”
Quote in the paperSubstantial claim - Findingown data
Expression of recombinant ARH in WIF-B cells did not affect the distribution of endogenous LDLR, clathrin or AP-2.
“Expression of recombinant ARH in WIF-B cells did not affect the distribution of endogenous LDLR, clathrin or AP-2”
Quote in the paperSubstantial claim - Findingown data
Quantification of immunogold particles on the cell surface reveals a ~33-fold increase in the number of LDLRs/μm of coated pit membrane in cells co-expressing LDLR and ARH.
“The quantification of immunogold particles on the cell surface revealed a ϳ33fold increase in the number of LDLRs/m of coated pit membrane (TABLE ONE).”
Quote in the paperSubstantial claim - Findingown data
ARH-induced clustering of LDLR into clathrin-coated pits failed to occur unless the PTB domain was present with at least one of two protein interacting motifs in the C-terminal portion of the protein, the clathrin box or the AP-2 binding sequence.
“ARH-induced clustering of LDLR into clathrin-coated pits failed to occur unless the PTB domain was present with at least one of two protein interacting motifs in the C-terminal portion of the protein, the clathrin box or the AP-2 binding sequence.”
Quote in the paperSubstantial claim - Findingown data
In cells expressing both LDLR and wild-type ARH, most receptors are internalized.
“In contrast, most receptors were internalized in cells expressing both LDLR and wild-type ARH.”
Quote in the paperSubstantial claim - Findingown data
The recombinant human LDLR expressed in WIF-B cells is expressed only on the basolateral membrane.
“The human LDLR was expressed only on the basolateral membrane (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
Mutant forms of ARH that promote receptor clustering also promote internalization.
“The mutant forms of ARH that promoted receptor clustering also promoted internalization (Fig. 9).”
Quote in the paperSubstantial claim - Findingown data
Recombinant ARH with mutations in the clathrin box (L212A/L213A) or in the AP-2 binding site (R266A) decreased plasma cholesterol to levels similar to wild-type ARH in Arh-/- mice.
“recombinant ARH with mutations in the clathrin box (AdARH-L212A/ L213A) or in the AP-2 binding site (ARH-R266A) decreased plasma cholesterol to levels similar to those of mice infected with the wild-type ARH adenovirus.”
Quote in the paperSubstantial claim - Findingown data
Mutant ARH proteins that fail to support LDLR clustering (S117Y, LL/AA/R266A) also fail to support receptor internalization.
“Moreover the mutant ARH protein that failed to support LDLR clustering (S117Y, LL/AA/R266A) also failed to support receptor internalization.”
Quote in the paperSubstantial claim - Findingown data
Expression of recombinant ARH in WIF-B cells markedly altered the distribution of recombinant LDLR.
“but markedly altered the distribution of recombinant LDLR (Figs. 3 and 4).”
Quote in the paperSubstantial claim - Findingown data
The ARH-induced changes in the cellular distribution of LDLR required a functional internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR.
“The ARH-induced changes in the cellular distribution of LDLR required a functional internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR”
Quote in the paperSubstantial claim - Findingown data
The integrity of the FDNPVY sequence in the cytoplasmic tail of the LDLR was required for ARH-mediated clustering and internalization of the LDLR in WIF-B cells.
“The integrity of the FDNPVY sequence in the cytoplasmic tail of the LDLR was required for ARH-mediated clustering and internalization of the LDLR in WIF-B cells.”
Quote in the paperSubstantial claim - Findingown data
The hypercholesterolemia of Arh-/- mice was ameliorated by adenoviral-mediated hepatic expression of wild-type ARH.
“The hypercholesterolemia of Arh Ϫ/Ϫ mice was ameliorated by adenoviral-mediated hepatic expression of wild-type ARH”
Quote in the paperSubstantial claim- Rests on an assumption: Adenoviral-mediated hepatic expression of ARH in Arh-/- mice reconstitutes ARH function in a physiologically relevant manner.
- Findingown data
Adenovirus-mediated expression of recombinant LDLR in WIF-B cells recapitulated the cell surface pattern of expression of the endogenous receptors in these cells.
“Adenovirus-mediated expression of recombinant LDLR in WIF-B cells recapitulated the cell surface pattern of expression of the endogenous receptors in these cells.”
Quote in the paperNot a substantial claim - Findingown data
Immunoelectron microscopy confirmed that most LDLR were located outside of coated pits in WIF-B cells.
“Immunoelectron microscopy confirmed that most of the receptors were located outside of coated pits”
Quote in the paperSubstantial claim - Findingown data
Expression of wild-type ARH in Arh-/- mice fed the high-fat diet was associated with a 50% reduction in circulating plasma cholesterol.
“Expression of wild-type ARH in these mice was associated with a 50% reduction in circulating levels of plasma cholesterol”
Quote in the paperSubstantial claim- Rests on an assumption: Plasma cholesterol levels reflect hepatic LDL clearance.
- Findingown data
In WIF-B cells co-expressing LDLR and ARH, gold-labeled LDLR density was higher on coated pit membrane (3.36 gold/μm) than on non-coated pit membrane (0.10 gold/μm).
“LDLRϩARH 25 502 50 0.10 25 84 3.36”
Quote in the paperSubstantial claim- Rests on an assumption: Immunogold labeling density on EM sections quantitatively reflects the surface distribution of LDLR.
- Findingown data
ARH promotes clustering of LDLR into clathrin-coated pits on the basolateral membrane of hepatocytes.
“A major finding of this study is that ARH promotes clustering of LDLR into clathrin-coated pits on the basolateral membrane of hepatocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: WIF-B cells are a valid model of hepatocyte LDLR trafficking.
- Findingown data
ARH-F165A failed to rescue ARH activity in Arh-/- mice.
“but failed to rescue ARH activity in the knock-out mice (Fig. 10).”
Quote in the paperSubstantial claim - Findingown data
In WIF-B cells expressing LDLR and β-galactosidase, immunogold particles are almost exclusively localized on the cell surface.
“In the WIF-B cells expressing LDLR and -galactosidase the immunogold particles were almost exclusively localized on the cell surface (Fig. 6A)”
Quote in the paperSubstantial claim - Findingown data
ARH-mediated LDLR clustering was accompanied by an increase in receptor internalization.
“ARH-mediated LDLR clustering was accompanied by an increase in receptor internalization.”
Quote in the paperSubstantial claim - Findingown data
The number of LDLRs per micrometer of plasma membrane is reduced ~9-fold in cells expressing both ARH and LDLR.
“The number of LDLRs per micrometer of plasma membrane was reduced ϳ9-fold in cells expressing both ARH and the LDLR.”
Quote in the paperSubstantial claim - Findingown data
Cells expressing LDLR-Y807A and ARH fail to internalize.
“Interaction of ARH with the LDLR was required, because cells expressing LDLR-Y807A and ARH failed to internalize.”
Quote in the paperSubstantial claim - Findingown data
A subset of plasma membrane associated LDLR appeared to co-localize with AP-2 or clathrin in WIF-B cells.
“and a subset appeared to co-localize with AP-2 or clathrin (Fig. 2).”
Quote in the paperNot a substantial claim - Findingown data
Membrane-associated recombinant ARH co-localizes extensively with AP-2 and clathrin-HC in WIF-B cells.
“The membrane-associated recombinant ARH appeared to co-localize extensively with AP-2 and clathrin-HC (Fig. 3).”
Quote in the paperNot a substantial claim - Findingown data
In mice expressing ARH-F165A or ARH-S117Y, plasma LDL-C levels actually increased.
“since the plasma level of LDL-C actually increased.”
Quote in the paperSubstantial claim - Findingown data
In cells expressing LDLR but no ARH, gold-LDL particles are mainly localized on the cell surface.
“In cells expressing the LDLR but no ARH, the gold particles were mainly localized on the cell surface (Fig. 7A).”
Quote in the paperSubstantial claim - Findingown data
In the absence of ARH, LDLRs were diffusely distributed on the sinusoidal surfaces of polarized WIF-B cells.
“In the absence of ARH, LDLRs were diffusely distributed on the sinusoidal surfaces of polarized WIF-B cells.”
Quote in the paperSubstantial claim- Rests on an assumption: WIF-B cells are a valid model of hepatocyte LDLR trafficking.
- Premisecitation
Autosomal recessive hypercholesterolemia is caused by mutations in ARH.
“The disease is caused by mutations in ARH”
- Also stated in: § Abstract · plain
“Autosomal recessive hypercholesterolemia is caused by mutations in ARH”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Garcia, 2001, Science source
- Also stated in: § Abstract · plain
- Interpretationown data
Interaction between the PTB domain of ARH and the internalization sequence in the LDLR is required for clustering.
“This finding confirms that interaction between the PTB domain of ARH and the internalization sequence in the LDLR is required for clustering.”
Quote in the paperSubstantial claim - Interpretationown data
ARH-mediated clustering of the receptor is required for efficient clearance of LDL by the liver.
“and that ARH-mediated clustering of the receptor is required for efficient clearance of LDL by the liver.”
Quote in the paperSubstantial claim - Interpretationown data
The interaction between the PTB domain of ARH and the cytoplasmic tail of LDLR is essential for ARH to promote clustering of the LDLR.
“These data are consistent with the interaction between the PTB domain of ARH and the cytoplasmic tail of LDLR being essential for ARH to promote clustering of the LDLR.”
Quote in the paperSubstantial claim - Interpretationreasoning
Endogenous ARH in WIF-B cells failed to promote clustering of recombinant LDLRs.
“These findings indicated that endogenous ARH in WIF-B cells failed to promote clustering of recombinant LDLRs”
Quote in the paperSubstantial claim - Interpretationown data
With the exception of the F165A mutation, which prevented ARH function in vivo but not in WIF-B cells, the effects of ARH on plasma cholesterol levels in mice paralleled those obtained in WIF-B cells.
“Thus, with the exception of the F165A mutation, which prevented ARH function in vivo but not in WIF-B cells, the effects of ARH on plasma cholesterol levels in mice paralleled those obtained in WIF-B cells.”
Quote in the paperSubstantial claim - Premisecitation
LDLR endocytosis is not impaired in ARH-deficient fibroblasts.
“LDLR endocytosis is not impaired in ARH-deficient fibroblasts (6 -8)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
ARH associated with the plasma membrane is predominantly localized to clathrin-coated pits in WIF-B cells.
“suggesting that the ARH associated with the plasma membrane was predominantly, though not exclusively, localized to clathrin-coated pits in these cells (Fig. 1B).”
Quote in the paperSubstantial claim - Interpretationown data
ARH-mediated clustering of LDLRs is required for receptor internalization in WIF-B cells.
“These data are consistent with ARH-mediated clustering of LDLRs being required for receptor internalization in WIF-B cells”
Quote in the paperSubstantial claim - Interpretationown data
The ability of ARH to drive LDLR clustering in WIF-B cells requires the integrity of the FDNPVY internalization sequence in the LDLR cytoplasmic tail.
“Thus, the ability of ARH to drive LDLR clustering in the WIF-B cells required the integrity of the FDNPVY internalization sequence in the LDLR cytoplasmic tail.”
Quote in the paperSubstantial claim - Interpretationreasoning
ARH-mediated clustering of LDLR in clathrin-coated pits is not dependent on access to any single binding site in the coated pit.
“This finding suggests that ARH-mediated clustering of LDLR in clathrin-coated pits is not dependent on access to any single binding site in the coated pit.”
Quote in the paperSubstantial claim - Interpretationcitation
The results of the present study reiterate the different contributions of ARH to LDLR endocytosis in different cell types.
“The results of the present study reiterate the different contributions of ARH to LDLR endocytosis in different cells types.”
Quote in the paperSubstantial claim - Interpretationown data
The distribution of the recombinant LDLR on the cell surface resembles that of the endogenous LDLR protein in WIF-B cells.
“Thus, the distribution of the recombinant LDLR on the cell surface resembled that of the endogenous LDLR protein (Fig. 2B).”
Quote in the paperNot a substantial claim - Interpretationreasoning
The presence of multiple binding modules in ARH allows efficient clustering of LDLR through interaction with different components of the endocytic machinery.
“Rather, the presence of multiple binding modules in ARH allows efficient clustering of LDLR through interaction with different components of the endocytic machinery.”
Quote in the paperSubstantial claim - Interpretationown data
Sequences in the C-terminal half of ARH are required for ARH-mediated clustering of LDLR in coated pits.
“Thus, sequences in the C-terminal half of ARH are required for ARH-mediated clustering of LDLR in coated pits.”
Quote in the paperSubstantial claim - Interpretationown data
Expression of ARH results in a redistribution of LDLR from the non-coated pit portion of the plasma membrane to coated pits.
“Thus, the expression of ARH resulted in a redistribution of LDLR from the non-coated pit portion of the plasma membrane to coated pits.”
Quote in the paperSubstantial claim - Study design and conductown data
Overexpression of ARH does not change the total amount of LDLR in cells.
“because overexpression of ARH did not change the total amount of LDLR in cells (Fig. 4B).”
Quote in the paperSubstantial claim - Interpretationown data
The PTB domain, the clathrin box, and the AP-2 binding motif of ARH interact in a combinatorial fashion to promote the localization of LDLR to clathrin-coated pits and the clearance of circulating LDL by the liver.
“The results indicate that the PTB domain, the clathrin box, and the AP-2 binding motif of ARH interact in a combinatorial fashion to promote the localization of LDLR to clathrin-coated pits and the clearance of circulating LDL by the liver.”
Quote in the paperSubstantial claim- Rests on an assumption: The primary route of clearance of LDL from the plasma is by LDLR-mediated endocytosis in the liver.
- Interpretationown data
ARH promotes clustering of LDLR.
“suggesting that ARH promotes clustering of LDLR (Fig. 4A).”
Quote in the paperSubstantial claim - Premisecitation
In fibroblasts, LDLRs are located predominantly on the cell surface in clathrin-coated pits.
“In fibroblasts, LDLRs are located predominantly on the cell surface in clathrin-coated pits (1)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Goldstein, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The binding modules required for receptor clustering and internalization in WIF-B cells were also required to clear lipoproteins in vivo.
“the binding modules required for receptor clustering and internalization in WIF-B cells were also required to clear lipoproteins in vivo.”
Quote in the paperSubstantial claim - Interpretationcitation
The distribution of LDLR outside coated pits in WIF-B cells is similar to the distribution of LDLR in the livers of mice expressing a human LDLR transgene.
“which is similar to the distribution of LDLR in the livers of mice expressing a human LDLR transgene (22).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Pathak, 1990, J. Cell Biol. source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation
Chow-fed Arh-/- mice are only mildly hypercholesterolemic.
“Because chow-fed Arh Ϫ/Ϫ mice are only mildly hypercholesterolemic (9)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Jones, 2003, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
ARH promotes the clustering of LDLRs on the cell surface of hepatocytes by coupling the cytoplasmic tail of the receptor to structural components of the clathrin-coated pit (clathrin and AP-2).
“Taken together, these data indicate that ARH promotes the clustering of LDLRs on the cell surface of hepatocytes by coupling the cytoplasmic tail of the receptor to structural components of the clathrin-coated pit (clathrin and AP-2)”
Quote in the paperSubstantial claim - Interpretationown data
The structural requirements for ARH function observed in hepatocytes were corroborated for the first time by reconstitution studies in Arh-/- mice.
“The structural requirements for ARH function observed in hepatocytes were corroborated for the first time by reconstitution studies in Arh Ϫ/Ϫ mice.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 18
- Probably not a substantial claim. 7
It may state two separate claims as one.
PremisecitationARH encodes a putative adaptor protein that interacts with the cytoplasmic tail of the LDLR, phospholipids, and clathrin and AP-2 in vitro.
“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.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [11] Mishra, 2002, Proc. Natl. Acad. Sci. U. S. A. source
- cites [13] He, 2002, J. Biol. Chem. source
The Abstract and Discussion report in vitro binding of ARH to the LDLR cytoplasmic tail, clathrin, and the β2-adaptin subunit of AP-2, consistent with its proposed adaptor role. Our copy does not report ARH binding to phospholipids; searches for phospholipids, phosphoinositides, and lipid binding did not find support for that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationARH is essential for normal LDLR endocytosis in transformed lymphocytes, but not in fibroblasts.
“Previous studies have demonstrated that ARH is essential for normal LDLR endocytosis in transformed lymphocytes, but not in fibroblasts (6, 7).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Norman, 1999, J. Clin. Investig. source
The Analysis of LDL receptor function reports that EBV-transformed lymphoblasts from two patients could not internalize LDL receptors. But the Discussion says the responsible gene had not yet been identified and explicitly leaves open whether the defect occurs in other tissues. The paper therefore does not establish that ARH is essential for endocytosis or that fibroblasts do not require it; no page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [7] Wilund, 2002, Hum. Mol. Genet. source
It may state two separate claims as one.
PremisecitationIn lymphocytes of subjects with ARH, a similar redistribution of LDLRs to the plasma membrane occurs, resulting in a 16-fold increase in cell surface receptor number.
“In lymphocytes of subjects with ARH, a similar redistribution of LDLRs to the plasma membrane occurs, resulting in a 16-fold increase in cell surface receptor number (10).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Michaely, 2004, J. Biol. Chem. source
It may state two separate claims as one.
PremisecitationAmino acids 44-178 of ARH encode a PTB domain that binds the FDNPVY sequence in the LDLR cytoplasmic tail and phosphoinositides.
“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).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [11] Mishra, 2002, Proc. Natl. Acad. Sci. U. S. A. source
- cites [13] He, 2002, J. Biol. Chem. source
The Results identify the ARH PTB domain as residues 45–175, close to the claimed 44–178. The Discussion reports that this domain binds the LDLR cytoplasmic tail through its NPVY motif and models an interaction with FDNPVY. Our copy does not report phosphoinositide binding by ARH; a search for phosphoinositides and phosphatidylinositol found no supporting passage. (LLM, conf=0.88)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationIn wild-type mice, approximately two-thirds of the hepatic LDLRs are intracellular, whereas in Arh-/- mice the majority of immunodetectable LDLRs are located on the sinusoidal membrane.
“In wild-type mice, approximately two-thirds of the hepatic LDLRs are intracellular, whereas in Arh Ϫ/Ϫ mice the majority of immunodetectable LDLRs are located on the sinusoidal membrane (9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Jones, 2003, J. Biol. Chem. source
The Results (page unavailable) report intracellular and cell-surface LDLR staining in wild-type liver, while LDLR in Arh−/− liver was sequestered virtually exclusively at the sinusoidal membrane. Our copy does not quantify the intracellular share in wild-type mice, so it does not support the approximately two-thirds figure. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
FindingcitationPlasma membrane associated LDLR were located on the basolateral (sinusoidal) membrane in WIF-B cells.
“Plasma membrane associated LDLR were located on the basolateral (sinusoidal) membrane as previously observed (26)”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Koivisto, 2001, Cell source
It may state two separate claims as one.
Findingown dataCo-expression of ARH and the LDLR in WIF-B cells resulted in LDL clustering and a major redistribution of the LDLR from the cell surface to internal vesicular compartments.
“Co-expression of ARH and the LDLR in the WIF-B cells not only resulted in LDL clustering but also in a major redistribution of the LDLR from the cell surface to internal vesicular compartments.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataRecombinant ARH in WIF-B cells is predominantly cytoplasmic, with some signal at the plasma membrane.
“The recombinant ARH was predominantly cytoplasmic but some signal was also apparent at the plasma membrane.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataIn polarized WIF-B cells, the plasma membrane-associated LDLR is located on the basolateral surfaces and only partially co-localizes with AP-2 or clathrin-HC.
“The plasma membrane-associated LDLR was located on the basolateral surfaces and only partially co-localized with AP-2 or with clathrin-HC (Fig. 1A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn WIF-B cells infected with AdLDLR and AdβGal, immunogold labeling of LDLR shows an even distribution along the plasma membrane with most staining outside clathrin-coated pits.
“In WIF-B cells infected with AdLDLR and AdGal, the immunogold labeling of LDLR showed an even distribution along the plasma membrane with most of the staining outside the clathrin-coated pits (Fig. 5).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingnone givenThe pattern of expression of recombinant ARH in WIF-B cells appeared similar to that of the endogenous ARH.
“The pattern of expression of recombinant ARH in WIF-B cells also appeared similar to that of the endogenous ARH.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataCo-expression of ARH results in clustering of LDLR in cells expressing wild-type LDLR but not in cells expressing LDLR-Y807A.
“Co-expression of ARH resulted in clustering of the LDLR in cells expressing wild-type LDLR but not in the cells expressing LDLR-Y807A (Fig. 4A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataHigh level expression of ARH in WIF-B cells did not interfere with LDLR clustering or internalization.
“High level expression of ARH in WIF-B cells did not interfere with LDLR clustering or internalization.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationLDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with autosomal recessive hypercholesterolemia.
“LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with this disorder.”
- Also stated in: § Abstract · plain
“Although LDL degradation is reduced in the liver (5) and in immortalized lymphocytes (6,7), cultured fibroblasts from patients with autosomal recessive hypercholesterolemia internalize and degrade LDL at normal or only modestly reduced rates (8).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [8] Zuliani, 1995, Eur. J. Clin. Investig. source
- Rests on an assumption: The primary route of clearance of LDL from the plasma is by LDLR-mediated endocytosis in the liver.
- Also stated in: § Abstract · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe static morphological techniques employed in this study prevented defining the temporal sequence of interactions between ARH, the LDLR and proteins/lipids in the coated pits.
“Because of the static morphological techniques employed in this study, we were unable to define the temporal sequence of the interactions between ARH, the LDLR and proteins/lipids in the coated pits.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductreasoningThe study cannot determine whether the ARH-mediated increase in LDLR internalization is simply a consequence of increased receptor clustering in clathrin-coated pits or whether ARH also has a direct effect on internalization once the receptor reaches coated pits in hepatocytes.
“Because we have yet to identify a mutation in ARH or in the LDLR that uncouples receptor clustering from receptor internalization, we cannot determine whether the ARH-mediated increase in LDLR internalization is simply a consequence of increased receptor clustering in clathrin-coated pits or whether ARH also has a direct effect on the internalization of the receptor once it reaches coated pits in”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe experiments were repeated five times with similar results.
“The experiments were repeated five times with similar results.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataBoth clustering and internalization require the conserved tyrosine at position 807 in the cytoplasmic tail of the LDLR.
“and that both clustering and internalization require the conserved tyrosine at position 807 in the cytoplasmic tail of the LDLR.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe assembly and internalization of clathrin-coated vesicles involves a series of low-affinity interactions with components of the coated pit, several of which interact with multiple partners.
“These observations are consistent with the findings of McMahon and co-workers (39) that the assembly and internalization of clathrin-coated vesicles involves a series of low-affinity interactions with components of the coated pit, several of which interact with multiple partners.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Praefcke, 2004, EMBO J. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataDisruption of either the clathrin box or the AP-2 motif does not abolish localization of the LDLR in clathrin-coated pits.
“Thus, disruption of either the clathrin box or the AP-2 motif did not abolish localization of the LDLR in clathrin-coated pits.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenAnimal experiments were approved by the University of Texas Southwestern Medical Center Animal Care and Use Committee (IACUC) and performed according to federal animal welfare policies and regulations.
“Animal experiments were approved by the University of Texas Southwestern Medical Center Animal Care and Use Committee (IACUC) and were performed according to all federal animal welfare policies and regulations.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataARH expression results in the clustering of LDLR in coated pits and promotes LDL internalization.
“Thus, ARH expression resulted in the clustering of LDLR in coated pits and promoted LDL internalization.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataARH must bind the LDLR tail and either clathrin or AP-2 to promote receptor clustering and internalization of LDL.
“These results demonstrate that ARH must bind the LDLR tail and either clathrin or AP-2 to promote receptor clustering and internalization of LDL.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The primary route of clearance of LDL from the plasma is by LDLR-mediated endocytosis in the liver.
“The primary route of clearance of LDL from the plasma is by LDL receptor (LDLR)-mediated endocytosis in the liver.”
The paper relies on this without support.
WIF-B cells are a valid model of hepatocyte LDLR trafficking.
“In the absence of ARH, LDLRs were diffusely distributed on the sinusoidal surfaces of polarized WIF-B cells.”
The paper relies on this without support.
The ARH mutations used (F165A, S117Y, L212A/L213A, R266A, LL/AA/R266A) affect only the intended binding interactions and not overall protein folding or stability.
“Expression of recombinant ARH constructs containing either the ARH-F165A or the ARH-S117Y mutations in the PTB domain failed to lower LDL-C levels”
The paper relies on this without support.
Plasma cholesterol levels reflect hepatic LDL clearance.
“Expression of wild-type ARH in these mice was associated with a 50% reduction in circulating levels of plasma cholesterol”
The paper relies on this without support.
Adenoviral-mediated hepatic expression of ARH in Arh-/- mice reconstitutes ARH function in a physiologically relevant manner.
“reconstitute hepatic ARH expression in Arh Ϫ/Ϫ mice (9)”
The paper relies on this without support.
Immunogold labeling density on EM sections quantitatively reflects the surface distribution of LDLR.
“Quantification of gold LDLRs on the surface of WIF-B cells using immunoelectron microscopy”
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?
Following lipoprotein binding, the LDLR adaptor protein ARH binds to the intracellular NPxY motif in the cytoplasmic tail of LDLR.
“Following lipoprotein binding, the LDLR adaptor protein autosomal recessive hypercholesterolemia protein93,94 (ARH) binds to the intracellular NPxY motif in the cytoplasmic tail of LDLR (Fig. 6A).”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [93]
The Results section (page unavailable) reports that the FDNPVY motif in the LDLR cytoplasmic tail binds recombinant ARH in vitro, and the Discussion says this interaction is required for ARH-mediated receptor clustering. The paper does not establish that ARH binds the motif *following lipoprotein binding*; its Discussion says the study could not define the temporal sequence of the interactions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDab2 appears to sort cargo into CCPs independently of AP2.
“it appears to sort cargo into CCPs independently of AP2 (Garuti et al., 2005; Keyel et al., 2006; Maurer and Cooper, 2006).”
From Cargo- and adaptor-specific mechanisms regulate clathrin-mediated endocytosis (2010) · cites this paper as Garuti et al., 2005
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.
The residue-165 mutant changes from F165A to Y165A
MinorThe mutant tested at residue 165 is identified as F165A, a phenylalanine-to-alanine substitution. A later passage calls the same mutant ARH-Y165A, which instead denotes a tyrosine-to-alanine substitution.
“Perhaps high level of expression of ARH-Y165A in WIF-B cells compensated for the reduced affinity of this mutant for the LDLR tail, and thereby supported LDLR clustering.”
“We first tested the effect of substituting alanine for phenylalanine at residue 165 (F165A) in the PTB domain of ARH”
Discussion incorrectly excludes ARH with both binding motifs
MinorThe discussion says clustering and internalization require either the clathrin box or the AP-2 binding motif, but not both. Yet the paper reports internalization with wild-type ARH, which has both motifs.
“an intact PTB domain together with either (but not both) a clathrin box or an AP-2 binding motif in ARH.”
“In contrast, most receptors were internalized in cells expressing both LDLR and wild-type ARH.”
Residue 117 is identified as both tyrosine and serine in wild-type ARH
MinorThe modeling passage identifies Tyr 117 as a conserved residue, but the described S117Y mutation substitutes tyrosine for the serine at position 117.
“two conserved aromatic residues (Tyr 117 and Phe 165 ) form a hydrophobic channel”
“we mutated the corresponding residue in the ARH (S117Y).”
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Metadata
- Authors
- Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., & Hobbs, H. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hobbs, Helen H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 280
- Issue
- 49
- Pages
- 40996-41004
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2011393081
- Semantic Scholar
- 8401ac95acc98620ce48d45436966cf9dbc21a27
- Cited by
- 91
- References
- 39
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 2 · 2015: 7 · 2014: 4 · 2013: 5 · 2012: 1
- FWCI
- 2.72
- 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 (R37HL063762, P01HL020948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- autosomal recessive hypercholesterolemia, LDL receptor, clathrin-coated pits, receptor clustering, receptor internalization, phosphotyrosine binding domain, adaptor protein 2, hepatocytes
- MeSH terms
- Animals, Binding Sites, Cell Fusion, Cell Line, Transformed, Cell Membrane, Clathrin, Cytoplasm, Fibroblasts, Fluorescent Antibody Technique, Humans, Microscopy, Fluorescence, Mutation, Receptors, LDL, Recombinant Proteins, Structure-Activity Relationship, Transfection, Gene Expression, Microscopy, Immunoelectron, Mice, Knockout, Clathrin-Coated Vesicles, Hepatocytes, Adaptor Protein Complex 2, Adaptor Proteins, Signal Transducing, Mice, Rats
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