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
- Interpretationcitation§ Abstract
LDLR function is markedly impaired in hepatocytes of ARH patients.
“This finding indicates that LDLR function is markedly impaired in the hepatocytes of ARH patients.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
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)
Experimental — accuracy not yet measured
- Premisecitation§ Abstract
Immortalized lymphoblasts from ARH patients have more LDLRs on the plasma membrane.
“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”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Norman, 1999, J. Clin. Invest. source
- Premisecitation§ Abstract
Autosomal recessive hypercholesterolemia is caused by defective internalization of LDL receptors in the liver.
“a disorder caused by defective internalization of low density lipoprotein receptors (LDLR) in the liver.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
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)
Experimental — accuracy not yet measured - cites [5] Norman, 1999, J. Clin. Invest. source
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)
Experimental — accuracy not yet measured
- Premisecitation§ Abstract
LDLR function is normal or only moderately reduced in fibroblasts from patients with ARH.
“In contrast, LDLR function is normal or only moderately reduced in fibroblasts from patients with this disorder (3”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
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)
Experimental — accuracy not yet measured - cites [4] Arca, 2002, Lancet source
- Premisecitation§ Abstract
Studies using plasmon resonance to test direct interactions between AP-2 and the FXNPXY motif of the LDLR tail have yielded contradictory results.
“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”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [13] Boll, 1996, EMBO J. source
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)
Experimental — accuracy not yet measured - cites [14] Boll, 2002, Traffic source
- Interpretationcitation§ DISCUSSION
Modeling of the ARH PTB domain 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.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Zhang, 1997, EMBO J. source
- 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.
- Premisecitation§ Abstract
LDL degradation is markedly reduced in transformed lymphocytes from ARH patients.
“Recently, LDL degradation was shown to be markedly reduced in transformed lymphocytes from ARH patients (5”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Norman, 1999, J. Clin. Invest. source
- Findingown data§ Abstract
Only ARH proteins that include residues 260-279 bind β2-adaptin.
“Only proteins that included residues 260–279 bound β2-adaptin.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Substitution of both the aspartic acid and glutamic acid residues of the ARH clathrin box with alanines abolishes binding to clathrin.
“Substitution of both the aspartic acid and glutamic acid residues with alanines also abolished binding.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mutation of Phe-165 in ARH to valine or alanine produced a protein that failed to bind the LDLR cytoplasmic tail.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The region of ARH comprising residues 260-279 is highly conserved between human, mouse, frog, and zebrafish.
“This region of ARH (residues 260–279) is highly conserved between human, mouse, frog, and zebrafish (Fig. 1)”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
The integrity of the NPVY sequence in the LDLR cytoplasmic tail is required for ARH binding.
“the integrity of the NPVY sequence is required for binding.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Full-length ARH and ARH 1-219 bind the clathrin terminal domain (residues 1-494 of the clathrin heavy chain).
“Full-length ARH and ARH 1–219 bound the clathrin terminal domain (Fig.5).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Replacement of tyrosine 807 with phenylalanine had no effect on the interaction between ARH and the LDLR tail.
“In contrast, the replacement of tyrosine 807 with phenylalanine had no effect on the interaction between ARH and the LDLR tail (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The PTB domain of ARH binds the cytoplasmic tail of the LDLR in vitro.
“In this paper we show that the PTB domain of ARH binds the cytoplasmic tail of the LDLR in vitro”
Quote in the paperSubstantial claim - Findingcitation§ Abstract
Residues 212-216 of human ARH (LLDLE) conform to the clathrin box consensus motif L(L/I)(D/E/N)(L/F)(D/E).
“Residues 212–216 of human ARH (LLDLE) conform to the clathrin box consensus motif L(L/I)(D/E/N)(L/F)(D/E)”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Mutation of a glutamic acid residue in the appendage domain of beta2-adaptin that is required for interaction with beta-arrestin markedly reduced binding to ARH.
“Mutation of a glutamic acid residue in the appendage domain of β2-adaptin that is required for interaction with the adapter protein β-arrestin markedly reduced binding to ARH.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Mutations in the NPVY sequence that were previously shown to decrease LDLR internalization abolished in vitro binding to ARH.
“Mutations in the NPVY sequence that were previously shown to decrease LDLR internalization abolished in vitro binding to ARH.”
Quote in the paperSubstantial claim - Findingnone given§ DISCUSSION
The sequences of ARH that mediate the interactions with the LDLR, clathrin, and β2-adaptin are highly conserved among humans, mice, frogs, and zebrafish.
“The sequences of ARH that mediate the interactions with these three proteins are highly conserved among humans, mice, frogs, and zebrafish”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
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.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
A highly conserved 20-amino acid sequence in the C-terminal region of ARH bound the beta2-adaptin subunit of AP-2.
“A highly conserved 20-amino acid sequence in the C-terminal region of ARH bound the β2-adaptin subunit of AP-2.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Fifty-four percent of the amino acids were identical in all four ARH proteins.
“Fifty-four percent of the amino acids were identical in all four proteins.”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
A conserved arginine residue, Arg-266, in ARH is required for binding to β2-adaptin.
“A conserved arginine residue, Arg-266, in this region is required for binding to β2-adaptin”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION
Mutation of Phe-165 in ARH to alanine or valine abolishes binding to the LDLR cytoplasmic tail.
“Mutation of Phe-165 in ARH to alanine or valine abolished binding to the LDLR cytoplasmic tail.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
ARH binds native clathrin purified from bovine brain with high affinity (dissociation constant ∼44 nM).
“Scatchard analysis (Fig.6) revealed that ARH bound clathrin with high affinity (dissociation constant, ∼44 nm).”
Quote in the paperSubstantial claim - Findingnone given§ DISCUSSION
Mutations in residues in the LDLR cytoplasmic tail that abolish LDL-mediated endocytosis also abolish binding to ARH.
“Mutations in residues in the LDLR cytoplasmic tail that abolish LDL-mediated endocytosis also abolish binding to ARH.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The PTB domain of ARH interacted with the internalization sequence NPVY in the cytoplasmic tail of LDLR in a sequence-specific manner.
“The phosphotyrosine binding domain of ARH interacted with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR in a sequence-specific manner.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Both Y807C and Y807A mutations in the LDLR tail markedly reduced binding of the LDLR cytoplasmic tail to ARH.
“Both mutations markedly reduced the binding of the LDLR cytoplasmic tail to ARH (Fig. 4).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Recombinant ARH bound purified bovine clathrin with high affinity (KD approximately 44 nM).
“Recombinant ARH bound purified bovine clathrin with high affinity (KD, ∼44 nm).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
No interaction was detected between the LDLR tail and an ARH fragment (residues 188-308) lacking the PTB domain.
“In contrast, no interaction was detected between the LDLR tail and an ARH fragment (residues 188–308) lacking the PTB domain.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
The rate at which LDL particles are cleared from plasma by the liver of ARH patients is as low as in patients with no functional LDLRs.
“The rate at which LDL particles are cleared from the plasma by the liver of ARH patients is as low as that in patients with no functional LDLRs (3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Zuliani, 1999, Arterioscler. Thromb. Vasc. Biol. source
- Premisecitation§ Abstract
Systematic mutagenesis of amino acids flanking Tyr-807 in the LDLR cytoplasmic tail indicates that the sequence FDNPVY functions as the internalization signal.
“Systematic mutagenesis of the amino acids flanking the Tyr-807 in the cytoplasmic tail of the LDLR indicates that the sequence FDNPVY functions as the internalization signal (9”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Abstract
Mutations in the phosphotyrosine binding domain protein ARH cause autosomal recessive hypercholesterolemia.
“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.”
- Also stated in: § Abstract · plain
“Autosomal recessive hypercholesterolemia is caused by mutations in a gene that encodes a phosphotyrosine binding (PTB)-domain protein called ARH (6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Garcia, 2001, Science source
- Also stated in: § Abstract · plain
- Premisecitation§ Abstract
The cytoplasmic tail of the LDLR contains an NPVY sequence that is required for LDLR-mediated endocytosis.
“The cytoplasmic tail of the LDLR contains an NPVY sequence that is required for LDLR-mediated endocytosis (9”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ Abstract
ARH binds the same domain on β2-adaptin that is bound by the nonvisual arrestins.
“These data indicate that ARH binds the same domain on β2-adaptin that is bound by the nonvisual arrestins”
Quote in the paperSubstantial claim - Interpretationcitation§ Abstract
Phosphorylation of residue 807 is not required for internalization.
“and that phosphorylation of this residue is not required for internalization.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The findings are consistent with the hypothesis that ARH is a modular adaptor protein that couples LDLR to the endocytic machinery.
“These findings are consistent with the hypothesis that ARH is a modular adaptor protein that couples LDLR to the endocytic machinery.”
- Also stated in: § Abstract · hedged
“These data are consistent with the hypothesis that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro interactions of recombinant ARH with LDLR, clathrin, and AP-2 reflect the interactions that mediate LDLR endocytosis in vivo.
- Also stated in: § Abstract · hedged
- Interpretationnone given§ DISCUSSION
ARH has a modular architecture consisting of at least four blocks of residues that show strong evolutionary conservation.
“ARH has a modular architecture consisting of at least four blocks of residues that show strong evolutionary conservation.”
Quote in the paperNot a substantial claim - Premisecitation§ Abstract
NMR studies reveal that peptides containing the NPVY sequence of LDLR adopt a reverse turn conformation, with asparagine at position i and tyrosine at position i+3 of the turn.
“Nuclear magnetic resonance studies reveal that peptides containing the NPVY sequence of LDLR adopt a reverse turn conformation, with the asparagine in position i and the tyrosine in position i + 3 of the turn (12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Bansal, 1991, Cell source
- Interpretationown data§ Abstract
The clathrin box motif of ARH mediates binding to the N-terminal domain of the clathrin heavy chain.
“These data indicate that the clathrin box motif of ARH mediates binding to the N-terminal domain of the clathrin heavy chain and that ARH binds native clathrin with high affinity.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
ARH can bind to the same region of AP-2 that is required for β-arrestin-mediated targeting of β-adrenergic receptors to clathrin-coated pits.
“These results suggest that ARH can bind to the same region of AP-2 that is required for β-arrestin-mediated targeting of β-adrenergic receptors to clathrin-coated pits.”
Quote in the paperSubstantial claim - Interpretationcitation§ Abstract
ARH is required for efficient LDLR-mediated endocytosis in transformed lymphocytes from ARH patients.
“indicating that ARH is required for efficient LDLR-mediated endocytosis in these cells.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The ARH-β2-adaptin interaction involves at least one of the glutamic acid residues (Glu-849) in the appendage domain of β2-adaptin.
“this interaction involves at least one of the glutamic acid residues (Glu-849) in the appendage domain of β2-adaptin.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Two highly conserved aromatic residues (Tyr-118 and Phe-165) of the ARH PTB domain are predicted to form a hydrophobic channel that cradles the peptide backbone of the FDNPVY sequence.
“Two highly conserved aromatic residues (Tyr-118 and Phe-165) of the ARH PTB domain are predicted to form a hydrophobic channel that cradles the peptide backbone of the FDNPVY sequence.”
Quote in the paperSubstantial claim- 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.
- Interpretationown data§ DISCUSSION
The ARH PTB domain maintains a binding mode similar to that seen in X11, SHC, and IRS-1.
“This finding suggests that the ARH PTB domain maintains a similar binding mode to that seen in X11, SHC, and IRS-1.”
Quote in the paperNot a substantial claim - Interpretationown data§ Abstract
The interaction between ARH and the LDLR tail requires an aromatic residue at position 807.
“These data taken together suggest that the interaction between ARH and the LDLR tail requires an aromatic residue at position 807”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
ARH contains a functional clathrin box sequence that may participate in the recruitment or retention of LDLR to clathrin-coated pits.
“These data suggest that ARH contains a functional clathrin box sequence that may participate in the recruitment or retention of LDLR to clathrin-coated pits by ARH.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Peptides derived from receptors that are defective in internalization do not adopt the reverse turn.
“In contrast, peptides derived from receptors that are defective in internalization do not adopt the reverse turn (12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Bansal, 1991, Cell source
- Interpretationown data§ DISCUSSION
ARH functions as an adaptor protein that links the LDLR to the endocytic machinery of the coated pit.
“Taken together, these data strongly support the hypothesis that ARH functions as an adaptor protein that links the LDLR to the endocytic machinery of the coated pit.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Binding of the ARH PTB domain to the LDLR cytoplasmic tail requires an aromatic amino acid in the fourth position of the NPVY sequence.
“These data suggest that the PTB domain of ARH binds to the LDLR cytoplasmic tail and that this binding requires an aromatic amino acid in the fourth position of the NPVY sequence.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 19
- Probably not a substantial claim. 8
It may state two separate claims as one.
Premisecitation§ AbstractIn immortalized lymphoblasts from ARH patients, LDL degradation is decreased by approximately 75% compared with normal individuals despite increased cell surface binding of LDL.
“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”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] Norman, 1999, J. Clin. Invest. source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractThe adaptor protein AP-2 binds other receptors that are internalized via clathrin-coated pits.
“The adaptor protein AP-2 has been shown to bind other receptors that are internalized via clathrin-coated pits”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractPeptides containing the sequence FDNPVY bind the terminal domain of clathrin in vitro.
“Peptides containing the sequence FDNPVY will bind the terminal domain of clathrin in vitro (15”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [15] Kibbey, 1998, J. Cell Biol. source
It may state two separate claims as one.
Findingown data§ AbstractMutation of Arg-261 does not significantly affect ARH binding to β2-adaptin, whereas mutation of Arg-266 to alanine completely abolishes binding.
“Mutation of Arg-261 did not significantly affect binding to β2-adaptin, whereas mutation of Arg-266 to alanine completely abolished binding.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ AbstractTruncation of ARH before the clathrin box (residue 212) or replacement of the first two leucine residues of the clathrin box with alanine residues abolishes binding to clathrin.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ AbstractARH can interact with the appendage domain of β2-adaptin, and this interaction requires one of the glutamic acid residues (Glu-849) in β2-adaptin that mediate binding to β-arrestin.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ AbstractMutation of Glu-849 in β2-adaptin to alanine abolishes binding to ARH, whereas mutation of Glu-902 reduces but does not abolish binding.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSThe mouse, frog, and zebrafish genomes encode proteins that share 89%, 72%, and 61% sequence identity with human ARH, respectively.
“The mouse, frog, and zebrafish genomes encode proteins that share 89, 72, and 61% sequence identity with human ARH, respectively (Fig.1).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ AbstractARH binds residues 664-937 of β2-adaptin but not a fragment containing the N-terminal 587 residues of β2-adaptin.
“ARH bound residues 664–937 of β2-adaptin but not to a fragment containing the N-terminal 587 residues of the protein.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ DISCUSSIONARH binds the LDLR cytoplasmic tail as well as the heavy chain of clathrin and the β2-adaptin subunit of AP-2.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ DISCUSSIONSubstitution of the tyrosine in the NPVY motif (Tyr-807) with alanine or cysteine markedly reduces the ARH-LDLR tail interaction, whereas introduction of phenylalanine at this position does not alter the interaction.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSFour major regions of sequence conservation were identified in ARH: 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), and a 27-amino acid sequence corresponding to residues 249-276 of human ARH.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Dell'Angelica, 2001, Trends Cell Biol. source
It may state two separate claims as one.
Findingown data§ RESULTSFull-length ARH and a fragment containing the PTB domain (residues 1-219) bound the LDLR tail.
“Full-length ARH and a fragment containing the PTB domain (residues 1–219) bound the LDLR tail (Fig.2 A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ AbstractThe region of ARH 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Premisecitation§ AbstractPTB domains of adaptor proteins such as SHC, IRS-1, X11, Dab-1, and Dab-2 bind a canonical NPXY sequence motif in cytoplasmic tails of various cell surface receptors.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Forman-Kay, 1999, Curr. Opin. Struct. Biol. source
- Also stated in: § RESULTS · plain
Probably not a substantial claim. It may state two separate claims as one.
Premisecitation§ AbstractReductions in hepatic LDLR activity result in elevated plasma LDL-cholesterol concentrations and deposition of cholesterol in body tissues.
“Reductions in hepatic LDLR activity result in elevated plasma LDL-cholesterol concentrations and the deposition of cholesterol in body tissues (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.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractPTB domains are found in several adaptor proteins that link proteins into functional complexes to orchestrate transmembrane signaling and endocytosis.
“PTB domains are found in several adaptor proteins that link proteins into functional complexes to orchestrate transmembrane signaling and endocytosis (7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Guy, 2002, Cell. Signal. source
Probably not a substantial claim. It may state two separate claims as one.
Premisecitation§ AbstractIn fibroblasts, LDLRs cluster on the cell surface in clathrin-coated pits that invaginate and detach from the plasma membrane as coated vesicles.
“In fibroblasts, LDLRs cluster on the cell surface in clathrin-coated pits that invaginate and detach from the plasma membrane as coated vesicles (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.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractLDL receptor-mediated endocytosis in the liver is the primary pathway for clearance of circulating LDL.
“LDL receptor (LDLR)-mediated endocytosis in the liver is the primary pathway for the clearance of circulating LDL (1”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Goldstein, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ AbstractA naturally occurring Y807C mutation in the LDLR NPVY motif prevents LDLRs from clustering, and receptors in cells from this patient are distributed diffusely over the cell surface.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Davis, 1986, Cell source
It may state two separate claims as one.
Interpretationown data§ AbstractEvolutionarily 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 beta2-adaptin subunit of AP-2.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationcitation§ AbstractThe NPVY sequence plays a conformational role critical for endocytosis of the LDLR, presumably by mediating binding to adaptor proteins.
“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.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ AbstractLDL uptake in fibroblasts from ARH patients is normal or only moderately impaired.
“LDL uptake in fibroblasts from ARH patients is normal or only moderately impaired (4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Arca, 2002, Lancet source
It may state two separate claims as one.
Study design and conductreasoning§ AbstractBecause 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 these interactions are important for ARH function.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractThe clathrin box consensus motif mediates binding of various proteins to the terminal domain of the clathrin heavy chain.
“that mediates binding of various proteins to the terminal domain of the clathrin heavy chain (18”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Dell'Angelica, 2001, Trends Cell Biol. source
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?
ARH 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.”
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 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 measuredResidues 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).”
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 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 measuredAmino 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).”
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 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 measuredThe cytosolic tails of sortilin and APP interact via the FLVHRY motif of sortilin with the YNPTYKFFE motif in APP, which overlaps with the ARH binding consensus YENPTY.
“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]
The Results (page unavailable) identify an APP peptide containing YENPTY, and the Discussion reports that ARH binds the LDL receptor tail through an NPVY-containing sequence. The paper does not establish YENPTY as an ARH-binding consensus or report an interaction between the cytosolic tails of sortilin and APP via FLVHRY and YNPTYKFFE. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe PTB domain of ARH binds to the unphosphorylated FDNPVY internalization sequence in LDLR in a sequence-specific manner.
“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).”
ARH contains a highly conserved sequence at its C terminus that binds the β2-subunit of AP2.
“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 clathrin box sequence in ARH can mediate high affinity binding to the heavy chain of clathrin.
“The clathrin box sequence in ARH can mediate high affinity binding to the heavy chain of clathrin (8,9).”
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).”
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 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).”
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 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).”
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]
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).”
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]
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.”
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 majority of studies so far available have been carried out on lymphocytes from ARH patients, in which the LDLR function is significantly impaired.
“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).”
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.
“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.”
ARH co-immunoprecipitates with β-adaptin and Dab2 in HepG2 cells.
“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
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