ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2

He, Guocheng; Gupta, Sarita; Yi, Ming; Michaely, Peter; Hobbs, Helen H.; Cohen, Jonathan C.

doi:10.1074/jbc.m208539200

Cited by 202 publications

(191 citation statements)

References 32 publications

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“…The biological significance of the ARH pocket for Y 0 is perhaps best demonstrated by the J.D. genetic lesion of a single amino acid substitution at Y 0 on the LDLR tail (Y807C) that reduces binding (11) and leads to FH (6).…”

Section: Hypercholesterolemia-causing Mutations Destabilize the Arh-ldlrmentioning

confidence: 99%

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Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY 0 internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I -7 xF -5 xNPxY 0 QK +2 . The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y 0 ). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y 0 explains the distinctive ability of ARH to internalize proteins containing either FxNPxY 0 or FxNPxF 0 sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.lipoprotein | crystallography | trafficking | lipid metabolism

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Section: Hypercholesterolemia-causing Mutations Destabilize the Arh-ldlrmentioning

confidence: 99%

“…This domain can also simultaneously interact with cell membrane phosphoinositides (10) while specific sequences within the C-terminal region of ARH bind clathrin and its adaptor AP2 (10,11). Together, this set of interactions enables ARH to function as an endocytic adaptor for the clathrin-mediated endocytosis of LDLR in the liver.…”

mentioning

confidence: 99%

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…LDLR contains a distinct signal, FxNPxY, and the LDLR does not appear to depend on AP-2 for internalization to the same degree as does the TfR (Traub, 2003). ARH (Autosomal Recessive Hypercholesterolemia) and Dab2 have been suggested to interact with the FxNPxY of LDLR, in addition to AP-2 and clathrin, thereby recruiting LDLR to coated pits (He et al, 2002;Mishra et al, 2002;Nagai et al, 2003;Sorkin, 2004). Whether or not the internalization of EGFR is dependent on AP-2 is under discussion.…”

Section: Yxx ) and The Dileucine Based (Consensus Motifs [De]xxxl[li]mentioning

confidence: 99%

Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation

Grøvdal

Stang

Sorkin

et al. 2004

Experimental Cell Research

159

143

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“…Genetic defects in ARH impair endocytosis of low density lipoprotein receptors family members (22,33,34), thereby reducing cholesterol uptake and increasing plasma concentration of cholesterol. Of interest, biochemical, epidemiological, and genetic evidence have involved cholesterol metabolism in the regulation of A␤PP processing and the pathogenesis of AD (35)(36)(37)(38).…”

Section: Resultsmentioning

confidence: 99%

“…These changes in A␤PP cell surface levels in ARH-low cells reflect a physiological role for ARH in either A␤PP internalization, transport to the cell membrane, and/or shedding of the ectodomain by secretases (␣ and/or ␤). Although further work will be required to discriminate among these possibilities, our data nevertheless prove a function for ARH in A␤PP biology.Genetic defects in ARH impair endocytosis of low density lipoprotein receptors family members (22,33,34), thereby reducing cholesterol uptake and increasing plasma concentration of cholesterol. Of interest, biochemical, epidemiological, and genetic evidence have involved cholesterol metabolism in the regulation of A␤PP processing and the pathogenesis of AD (35-38).…”

mentioning

confidence: 99%

Autosomal Recessive Hypercholesterolemia Protein Interacts with and Regulates the Cell Surface Level of Alzheimer's Amyloid β Precursor Protein

Noviello

Vito

Lopez

et al. 2003

Journal of Biological Chemistry

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The familial Alzheimer's disease gene product amyloid ␤ protein precursor (A␤PP) is sequentially processed by ␤-and ␥-secretases to generate the A␤ peptide. Although much is known about the biochemical pathway leading to A␤ formation, because extracellular aggregates of A␤ peptides are considered the cause of Alzheimer's disease, the biological role of A␤PP processing is only recently being investigated. Cleavage of A␤PP by ␥-secretase releases, together with A␤, a COOH-terminal A␤PP intracellular domain, termed AID. Hoping to gain clues about proteins that regulates A␤PP processing and function, we used the yeast two-hybrid system to identify proteins that interact with the AID region of A␤PP. One of the interactors isolated is the autosomal recessive hypercholesterolemia (ARH) adapter protein. This molecular interaction is confirmed in vitro and in vivo by fluorescence resonance energy transfer and in cell lysates. Moreover, we show that reduction of ARH expression by RNA interference results in increased levels of cell membrane A␤PP. These data assert a physiological role for ARH in A␤PP internalization, transport, and/or processing. A␤PP1 is a ubiquitous type I transmembrane protein that undergoes extensive proteolytic processing along two major pathways (1-5). In the amyloidogenic pathway, A␤PP is cleaved in the ectodomain by the ␤-secretase forming a C99 membrane-bound intermediate. C99 can be cleaved by the ␥-secretase to release A␤ and the APP intracellular domain (AID). Alternatively, A␤PP can be cleaved within the A␤ sequence by the ␣-secretase creating a C83 membrane-bound intermediate which produces P3 and AID after ␥-cleavage. A␤PP processing is firmly associated with the pathogenesis of Alzheimer's disease (AD) because mutations associated with familial forms of AD are found in A␤PP itself and in the highly homologous genes PS1 and PS2, which are key components of a multimolecular complex with ␥-secretase activity (6 -15).Although the role of A␤ peptides in the pathogenesis of AD has been extensively studied, reports as to the role of AID are very recent. AID-like peptides have been identified in human brains from cases of sporadic AD (16) and play a role in apoptosis (16), transcription (17)(18)(19)(20), and Ca 2ϩ release from the endoplasmic reticulum (21).A␤PP processing and AID signaling can be regulated by A␤PP-interacting proteins (17)(18)(19)(20)(21)(22). Thus, to find A␤PP-binding proteins we employed the yeast two-hybrid selection system. This screening resulted in the identification of several proteins that bind the intracellular domain of A␤PP. Here we report the novel A␤PP interactor ARH, an adapter protein that has been shown to regulate cholesterol uptake by genetic studies (22). These data suggest that ARH may be a mediator of the well described effect of cholesterol metabolism on A␤PP processing. MATERIALS AND METHODSYeast Two-hybrid System-The two-hybrid screening was conducted using the Matchmaker system from Clontech according to the manufacturer's instruction. For library screen...

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ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2

Cited by 202 publications

References 32 publications

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation

Autosomal Recessive Hypercholesterolemia Protein Interacts with and Regulates the Cell Surface Level of Alzheimer's Amyloid β Precursor Protein

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