ARH_MOUSE
ID ARH_MOUSE Reviewed; 308 AA.
AC Q8C142; Q3TW86; Q6NWV6; Q8VDQ0;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Low density lipoprotein receptor adapter protein 1 {ECO:0000305};
DE AltName: Full=Autosomal recessive hypercholesterolemia protein homolog {ECO:0000305|PubMed:12746448};
GN Name=Ldlrap1 {ECO:0000312|MGI:MGI:2140175};
GN Synonyms=Arh {ECO:0000303|PubMed:12746448};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C3H/He, and CD-1;
RC TISSUE=Mammary gland, Neural stem cell, and Osteoblast;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND INTERACTION WITH LDLR AND VLDLR.
RX PubMed=12746448; DOI=10.1074/jbc.m304855200;
RA Jones C., Hammer R.E., Li W.-P., Cohen J.C., Hobbs H.H., Herz J.;
RT "Normal sorting but defective endocytosis of the low density lipoprotein
RT receptor in mice with autosomal recessive hypercholesterolemia.";
RL J. Biol. Chem. 278:29024-29030(2003).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=15166224; DOI=10.1074/jbc.m405242200;
RA Michaely P., Li W.-P., Anderson R.G.W., Cohen J.C., Hobbs H.H.;
RT "The modular adaptor protein ARH is required for low density lipoprotein
RT (LDL) binding and internalization but not for LDL receptor clustering in
RT coated pits.";
RL J. Biol. Chem. 279:34023-34031(2004).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-201, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Liver, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Adapter protein (clathrin-associated sorting protein (CLASP))
CC required for efficient endocytosis of the LDL receptor (LDLR) in
CC polarized cells such as hepatocytes and lymphocytes, but not in non-
CC polarized cells (fibroblasts). May be required for LDL binding and
CC internalization but not for receptor clustering in coated pits. May
CC facilitate the endocytosis of LDLR and LDLR-LDL complexes from coated
CC pits by stabilizing the interaction between the receptor and the
CC structural components of the pits. May also be involved in the
CC internalization of other LDLR family members. Binds to
CC phosphoinositides, which regulate clathrin bud assembly at the cell
CC surface. Required for trafficking of LRP2 to the endocytic recycling
CC compartment which is necessary for LRP2 proteolysis, releasing a tail
CC fragment which translocates to the nucleus and mediates transcriptional
CC repression (By similarity). {ECO:0000250|UniProtKB:D3ZAR1,
CC ECO:0000269|PubMed:12746448, ECO:0000269|PubMed:15166224}.
CC -!- SUBUNIT: Interacts (via PID domain) with LDLR (via NPXY motif). Binds
CC to soluble clathrin trimers. Interacts with AP2B1; the interaction
CC mediates the association with the AP-2 complex (By similarity).
CC Interacts with VLDLR (PubMed:12746448). Interacts with LRP2 (By
CC similarity). {ECO:0000250|UniProtKB:D3ZAR1,
CC ECO:0000250|UniProtKB:Q5SW96, ECO:0000269|PubMed:12746448}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15166224}.
CC -!- DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction
CC the AP-2 complex subunit AP2B1. {ECO:0000250|UniProtKB:Q5SW96}.
CC -!- DOMAIN: The PID domain mediates interaction with the NPXY
CC internalization motif of LDLR. {ECO:0000250|UniProtKB:D3ZAR1}.
CC -!- DISRUPTION PHENOTYPE: Mice are extremely sensitive to cholesterol
CC intake. LDLR are expressed at normal levels, but are sequestered at the
CC hepatocyte surface. LDL internalization defect is caused by the
CC inability of the LDLR to enter the endocytic cycle.
CC {ECO:0000269|PubMed:15166224}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH21467.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK029008; BAC26238.1; -; mRNA.
DR EMBL; AK148340; BAE28493.1; -; mRNA.
DR EMBL; AK159800; BAE35380.1; -; mRNA.
DR EMBL; AK167290; BAE39396.1; -; mRNA.
DR EMBL; AL645531; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466552; EDL30001.1; -; Genomic_DNA.
DR EMBL; BC021467; AAH21467.1; ALT_INIT; mRNA.
DR EMBL; BC066808; AAH66808.1; -; mRNA.
DR EMBL; BC067411; AAH67411.1; -; mRNA.
DR CCDS; CCDS51327.1; -.
DR RefSeq; NP_663529.2; NM_145554.2.
DR RefSeq; XP_006538486.1; XM_006538423.3.
DR AlphaFoldDB; Q8C142; -.
DR SMR; Q8C142; -.
DR BioGRID; 221366; 2.
DR STRING; 10090.ENSMUSP00000036749; -.
DR iPTMnet; Q8C142; -.
DR PhosphoSitePlus; Q8C142; -.
DR EPD; Q8C142; -.
DR jPOST; Q8C142; -.
DR MaxQB; Q8C142; -.
DR PaxDb; Q8C142; -.
DR PeptideAtlas; Q8C142; -.
DR PRIDE; Q8C142; -.
DR ProteomicsDB; 282016; -.
DR Antibodypedia; 30473; 567 antibodies from 35 providers.
DR Ensembl; ENSMUST00000037828; ENSMUSP00000036749; ENSMUSG00000037295.
DR GeneID; 100017; -.
DR KEGG; mmu:100017; -.
DR UCSC; uc012dmx.1; mouse.
DR CTD; 26119; -.
DR MGI; MGI:2140175; Ldlrap1.
DR VEuPathDB; HostDB:ENSMUSG00000037295; -.
DR eggNOG; KOG3536; Eukaryota.
DR GeneTree; ENSGT00940000157118; -.
DR HOGENOM; CLU_078253_0_0_1; -.
DR InParanoid; Q8C142; -.
DR OMA; NNSVVWE; -.
DR OrthoDB; 1531411at2759; -.
DR PhylomeDB; Q8C142; -.
DR TreeFam; TF314159; -.
DR Reactome; R-MMU-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-MMU-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-MMU-8964026; Chylomicron clearance.
DR Reactome; R-MMU-8964038; LDL clearance.
DR BioGRID-ORCS; 100017; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Ldlrap1; mouse.
DR PRO; PR:Q8C142; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q8C142; protein.
DR Bgee; ENSMUSG00000037295; Expressed in ear vesicle and 193 other tissues.
DR Genevisible; Q8C142; MM.
DR GO; GO:0030424; C:axon; ISO:MGI.
DR GO; GO:0009925; C:basal plasma membrane; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:MGI.
DR GO; GO:0005883; C:neurofilament; IDA:BHF-UCL.
DR GO; GO:0055037; C:recycling endosome; ISO:MGI.
DR GO; GO:0001540; F:amyloid-beta binding; IPI:BHF-UCL.
DR GO; GO:0035650; F:AP-1 adaptor complex binding; ISS:UniProtKB.
DR GO; GO:0035612; F:AP-2 adaptor complex binding; ISS:UniProtKB.
DR GO; GO:0035615; F:clathrin adaptor activity; ISO:MGI.
DR GO; GO:0030276; F:clathrin binding; ISS:UniProtKB.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISO:MGI.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISO:MGI.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISS:UniProtKB.
DR GO; GO:0035591; F:signaling adaptor activity; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; ISO:MGI.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; ISO:MGI.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; ISO:MGI.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:MGI.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:MGI.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0034383; P:low-density lipoprotein particle clearance; ISO:MGI.
DR GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISO:MGI.
DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; ISS:UniProtKB.
DR GO; GO:1905602; P:positive regulation of receptor-mediated endocytosis involved in cholesterol transport; ISO:MGI.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0031623; P:receptor internalization; ISO:MGI.
DR GO; GO:0006898; P:receptor-mediated endocytosis; ISO:MGI.
DR GO; GO:0090118; P:receptor-mediated endocytosis involved in cholesterol transport; ISO:MGI.
DR GO; GO:0043393; P:regulation of protein binding; ISO:MGI.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; ISO:MGI.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006020; PTB/PI_dom.
DR Pfam; PF14719; PID_2; 1.
DR SMART; SM00462; PTB; 1.
DR PROSITE; PS01179; PID; 1.
PE 1: Evidence at protein level;
KW Acetylation; Atherosclerosis; Cholesterol metabolism; Cytoplasm;
KW Endocytosis; Hyperlipidemia; Lipid metabolism; Phosphoprotein;
KW Reference proteome; Steroid metabolism; Sterol metabolism.
FT CHAIN 1..308
FT /note="Low density lipoprotein receptor adapter protein 1"
FT /id="PRO_0000064676"
FT DOMAIN 41..195
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT REGION 179..201
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 248..275
FT /note="AP-2 complex binding"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT REGION 288..308
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 211..215
FT /note="Clathrin box"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOTIF 256..265
FT /note="[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOD_RES 198
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:D3ZAR1"
FT MOD_RES 201
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CONFLICT 260
FT /note="R -> K (in Ref. 1; BAC26238)"
FT /evidence="ECO:0000305"
FT CONFLICT 296
FT /note="S -> G (in Ref. 4; AAH66808/AAH67411)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 308 AA; 33975 MW; 4183DA9594FD1F2C CRC64;
MDALKSAGRA LIRSPSLAKQ SWAGGRHRKL PENWTDTRET LLEGMVFSLK YLGMTLVERP
KGEELSAAAV KRIVATAKAS GKKLQKVTLK VSPRGIILTD SLTSQLIENV SIYRISYCTA
DKMHDKVFAY IAQSQQNESL ECHAFLCTKR KVAQAVTLTV AQAFKVAFEF WQVSKEEKEK
REKANQEGGD VPGTRRDSTP SLKTLVATGN LLDLEEVAKA PLSTVSANTN NVDETPRPQV
LGNNSVVWEL DDGLDEAFSR LAQSRTNPQV LDTGLSAQDI HYAQCLSPTD WDKPDSSGID
QDDDVFTF
