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Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytocis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression.
Gene References into Functions
LDLRAP1 associated with Familial Hypercholesterolemia and Polygenic Hypercholesterolemia in patients with Acute Coronary Syndrome , age =65 years, and LDL-C levels >/=160 mg/dl. PMID: 28958330
Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. PMID: 25331956
Identification of ARH gene and characterization of its mutations in Autosomal Recessive Hypercholesterolemia patients [Review] PMID: 25225128
cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide. PMID: 23564733
This work identified a combined LDL receptor and LDLRAP1 mutation as the cause for severe familial hypercholesterolemia in a family of Turkish descent. PMID: 23510778
The report provides evidence that endocytosis of the ROMK potassium channel is controlled by LDLRAP1 (ARH). ROMK binds directly to the LDLRAP1, and this interaction is mediated by a novel variant of the canonical "NPXY" endocytotic signal, YxNPxFV. LDLRAP1-knockout mice are unable to physiologically regulate ROMK. PMID: 19841541
report the crystal structure at 1.37-A resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY(0) internalization signal PMID: 22509010
LDL receptor/LDLRAP1 double heterozygous mutations may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in familial hypercholesterolemia patients. PMID: 21872251
ARH protein is involved in cell cycle progression, possibly by affecting nuclear membrane formation through interaction with lamin B1 or other mitotic proteins, and its absence affects cell proliferation and induces premature senescence. PMID: 21778424
Knockdown of ARH in polarized epithelial cells leads to specific apical missorting of truncated LDLR, which encodes only the FxNPxY motif (LDLR-CT27). PMID: 21444685
newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain of ARH; among 1,800 Japanese individuals, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia resembling familiar hypercholesterolemia PMID: 20124734
Report prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia. PMID: 19477448
ARH functions as an adaptor protein that couples LDLR to the endocytic machinery PMID: 12221107
The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. In ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia. PMID: 12451172
restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression PMID: 12464675
Single nucleotide polymorphism discovered among normal subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes proline residue at 202 to serine. ARH caused by mutation of cytosine to adenine at this same position. PMID: 12788851
ARH facilitates endocytosis of megalin, escorts megalin along its endocytic route PMID: 14528014
findings indicate that low density lipoprotein (LDL) receptor adaptor protein(ARH) is required not only for internalization of the LDL.LDL Receptor complex but also for efficient binding of LDL to the receptor PMID: 15166224
Splice site mutant lacks 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. PMID: 15599766
ARH protein has an AP-2 beta2 appendage-binding sequence PMID: 15728179
ARH is an endocytic sorting adaptor that actively participates in the internalization of the LDL-LDLR complex, possibly enhancing the efficiency of its packaging into the endocytic vesicles PMID: 16129683
Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss. PMID: 16870701
ARH might accelerate later steps in LDLR endocytosis in cooperation with AP-2. PMID: 16984970
Large deletion in the ARH gene is associated with autosomal recessive hypercholesterolemia PMID: 17686643
the endocytic adaptor protein ARH associates with motor and centrosomal proteins and is involved in centrosome assembly and cytokinesis PMID: 18417616
PCSK9-mediated LDLR degradation is not entirely dependent on ARH function PMID: 19081568
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Involvement in disease
Hypercholesterolemia, autosomal recessive (ARH)
Subcellular Location
Cytoplasm.
Tissue Specificity
Expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes.