ARH_RAT
ID ARH_RAT Reviewed; 306 AA.
AC D3ZAR1;
DT 30-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 2.
DT 03-AUG-2022, entry version 94.
DE RecName: Full=Low density lipoprotein receptor adapter protein 1 {ECO:0000305};
DE AltName: Full=Autosomal recessive hypercholesterolemia protein homolog {ECO:0000305|PubMed:22509010};
GN Name=Ldlrap1 {ECO:0000312|RGD:1563417};
GN Synonyms=Arh {ECO:0000303|PubMed:22509010};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [3]
RP FUNCTION, AND INTERACTION WITH LRP2.
RX PubMed=23836931; DOI=10.1083/jcb.201211110;
RA Shah M., Baterina O.Y. Jr., Taupin V., Farquhar M.G.;
RT "ARH directs megalin to the endocytic recycling compartment to regulate its
RT proteolysis and gene expression.";
RL J. Cell Biol. 202:113-127(2013).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.37 ANGSTROMS) OF 43-173 IN COMPLEX WITH LDLR,
RP INTERACTION WITH LDLR, DOMAIN, AND MUTAGENESIS OF THR-55.
RX PubMed=22509010; DOI=10.1073/pnas.1114128109;
RA Dvir H., Shah M., Girardi E., Guo L., Farquhar M.G., Zajonc D.M.;
RT "Atomic structure of the autosomal recessive hypercholesterolemia
RT phosphotyrosine-binding domain in complex with the LDL-receptor tail.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:6916-6921(2012).
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 (By similarity). Required for trafficking of LRP2 to the
CC endocytic recycling compartment which is necessary for LRP2
CC proteolysis, releasing a tail fragment which translocates to the
CC nucleus and mediates transcriptional repression (PubMed:23836931).
CC {ECO:0000250|UniProtKB:Q8C142, ECO:0000269|PubMed:23836931}.
CC -!- SUBUNIT: Interacts (via PID domain) with LDLR (via NPXY motifs)
CC (PubMed:22509010). Binds to soluble clathrin trimers (By similarity).
CC Interacts with AP2B1; the interaction mediates the association with the
CC AP-2 complex (By similarity). Interacts with VLDLR (By similarity).
CC Interacts with LRP2 (PubMed:23836931). {ECO:0000250|UniProtKB:Q5SW96,
CC ECO:0000250|UniProtKB:Q8C142, ECO:0000269|PubMed:22509010,
CC ECO:0000269|PubMed:23836931}.
CC -!- INTERACTION:
CC D3ZAR1; PRO_0000017322 [P98158]: Lrp2; NbExp=3; IntAct=EBI-9250714, EBI-9251342;
CC D3ZAR1; P01130: LDLR; Xeno; NbExp=3; IntAct=EBI-9250714, EBI-988319;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8C142}.
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:0000269|PubMed:22509010}.
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DR EMBL; AABR07050129; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PDB; 3SO6; X-ray; 1.37 A; A=43-173.
DR PDBsum; 3SO6; -.
DR AlphaFoldDB; D3ZAR1; -.
DR SMR; D3ZAR1; -.
DR DIP; DIP-60041N; -.
DR IntAct; D3ZAR1; 3.
DR STRING; 10116.ENSRNOP00000000163; -.
DR iPTMnet; D3ZAR1; -.
DR PaxDb; D3ZAR1; -.
DR PeptideAtlas; D3ZAR1; -.
DR PRIDE; D3ZAR1; -.
DR UCSC; RGD:1563417; rat.
DR RGD; 1563417; Ldlrap1.
DR VEuPathDB; HostDB:ENSRNOG00000000151; -.
DR eggNOG; KOG3536; Eukaryota.
DR HOGENOM; CLU_078253_0_0_1; -.
DR InParanoid; D3ZAR1; -.
DR OMA; NNSVVWE; -.
DR TreeFam; TF314159; -.
DR Reactome; R-RNO-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-RNO-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-RNO-8964026; Chylomicron clearance.
DR Reactome; R-RNO-8964038; LDL clearance.
DR PRO; PR:D3ZAR1; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000000151; Expressed in spleen and 18 other tissues.
DR Genevisible; D3ZAR1; RN.
DR GO; GO:0030424; C:axon; IDA:BHF-UCL.
DR GO; GO:0009925; C:basal plasma membrane; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISO:RGD.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0005769; C:early endosome; ISO:RGD.
DR GO; GO:0005883; C:neurofilament; ISO:RGD.
DR GO; GO:0055037; C:recycling endosome; ISO:RGD.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:RGD.
DR GO; GO:0035650; F:AP-1 adaptor complex binding; ISO:RGD.
DR GO; GO:0035612; F:AP-2 adaptor complex binding; ISO:RGD.
DR GO; GO:0035615; F:clathrin adaptor activity; ISO:RGD.
DR GO; GO:0030276; F:clathrin binding; ISO:RGD.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISO:RGD.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISO:RGD.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:RGD.
DR GO; GO:0035591; F:signaling adaptor activity; ISO:RGD.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; ISO:RGD.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; ISO:RGD.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:RGD.
DR GO; GO:0042632; P:cholesterol homeostasis; ISO:RGD.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0034383; P:low-density lipoprotein particle clearance; ISO:RGD.
DR GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISO:RGD.
DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; ISO:RGD.
DR GO; GO:1905602; P:positive regulation of receptor-mediated endocytosis involved in cholesterol transport; ISO:RGD.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:RGD.
DR GO; GO:0031623; P:receptor internalization; ISO:RGD.
DR GO; GO:0006898; P:receptor-mediated endocytosis; ISO:RGD.
DR GO; GO:0090118; P:receptor-mediated endocytosis involved in cholesterol transport; ISO:RGD.
DR GO; GO:0043393; P:regulation of protein binding; ISO:RGD.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; ISO:RGD.
DR Gene3D; 2.30.29.30; -; 1.
DR IDEAL; IID50263; -.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006020; PTB/PI_dom.
DR Pfam; PF00640; PID; 1.
DR SMART; SM00462; PTB; 1.
DR PROSITE; PS01179; PID; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cholesterol metabolism; Cytoplasm; Endocytosis;
KW Lipid metabolism; Phosphoprotein; Reference proteome; Steroid metabolism;
KW Sterol metabolism.
FT CHAIN 1..306
FT /note="Low density lipoprotein receptor adapter protein 1"
FT /id="PRO_0000438414"
FT DOMAIN 44..168
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT REGION 178..204
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 247..274
FT /note="AP-2 complex binding"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOTIF 210..214
FT /note="Clathrin box"
FT /evidence="ECO:0000250|UniProtKB:Q5SW96"
FT MOTIF 255..264
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 197
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 200
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C142"
FT MUTAGEN 55
FT /note="T->M: 10-fold reduced affinity for LDLR."
FT /evidence="ECO:0000269|PubMed:22509010"
FT STRAND 45..60
FT /evidence="ECO:0007829|PDB:3SO6"
FT HELIX 63..79
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 85..92
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 95..100
FT /evidence="ECO:0007829|PDB:3SO6"
FT TURN 101..103
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 106..111
FT /evidence="ECO:0007829|PDB:3SO6"
FT HELIX 112..114
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 115..123
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 126..132
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 134..137
FT /evidence="ECO:0007829|PDB:3SO6"
FT STRAND 139..145
FT /evidence="ECO:0007829|PDB:3SO6"
FT HELIX 149..171
FT /evidence="ECO:0007829|PDB:3SO6"
SQ SEQUENCE 306 AA; 33785 MW; FD73C718AED585F5 CRC64;
MDALKSAGRA LIRSPSLAKQ SWAGGRHRKL PENWTDTRET LLEGMVFSLK YLGMTLVERP
KGEELSAAAV KRIVATAKAS GKKLQKVTLK VSPRGIILTD SLTSQLIENV SIYRISYCTA
QMHDKVFAYI AQSQQNESLE CHAFLCTKRK VAQAVTLTVA QAFKVAFEFW QVSKEEKEKR
EKANQEGGDV PGTRRDSTPS LKTSVATGNL LDLEELAKAP LSTVSANTKN MDDALRPQVL
GNNSVVWELD DGLDEAFSRL AQSRTNPQVL DTGLTAQDIH YAQCLSPTDW DKPDSSGFDQ
DDVFSF
