AP2M1_HUMAN
ID AP2M1_HUMAN Reviewed; 435 AA.
AC Q96CW1; A6NE12; D3DNT1; P20172; P53679;
DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2004, sequence version 2.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=AP-2 complex subunit mu {ECO:0000305};
DE AltName: Full=AP-2 mu chain;
DE AltName: Full=Adaptin-mu2;
DE AltName: Full=Adaptor protein complex AP-2 subunit mu;
DE AltName: Full=Adaptor-related protein complex 2 subunit mu;
DE AltName: Full=Clathrin assembly protein complex 2 mu medium chain;
DE AltName: Full=Clathrin coat assembly protein AP50;
DE AltName: Full=Clathrin coat-associated protein AP50;
DE AltName: Full=HA2 50 kDa subunit;
DE AltName: Full=Plasma membrane adaptor AP-2 50 kDa protein;
GN Name=AP2M1 {ECO:0000312|HGNC:HGNC:564}; Synonyms=CLAPM1, KIAA0109;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Tsui S.K.W., Waye M.M.Y., Liew C.C., Fung K., Lee C.Y.;
RT "Molecular cloning and sequence analysis of the cDNA for human 50 kDa
RT subunit of the clathrin assembly complex AP-2 (AP50).";
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7788527; DOI=10.1093/dnares/2.1.37;
RA Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S.,
RA Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. III. The
RT coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:37-43(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney, Placenta, and Skin;
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 [7]
RP INTERACTION WITH RALBP1.
RX PubMed=10910768; DOI=10.1242/jcs.113.16.2837;
RA Jullien-Flores V., Mahe Y., Mirey G., Leprince C., Meunier-Bisceuil B.,
RA Sorkin A., Camonis J.H.;
RT "RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex:
RT involvement of the Ral pathway in receptor endocytosis.";
RL J. Cell Sci. 113:2837-2844(2000).
RN [8]
RP INTERACTION WITH ATP6V1H.
RX PubMed=12032142; DOI=10.1074/jbc.m200522200;
RA Geyer M., Yu H., Mandic R., Linnemann T., Zheng Y.-H., Fackler O.T.,
RA Peterlin B.M.;
RT "Subunit H of the V-ATPase binds to the medium chain of adaptor protein
RT complex 2 and connects Nef to the endocytic machinery.";
RL J. Biol. Chem. 277:28521-28529(2002).
RN [9]
RP FUNCTION, AND PHOSPHORYLATION AT THR-156.
RX PubMed=11877457; DOI=10.1083/jcb.200111068;
RA Ricotta D., Conner S.D., Schmid S.L., von Figura K., Honing S.;
RT "Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity
RT binding to membrane protein sorting signals.";
RL J. Cell Biol. 156:791-795(2002).
RN [10]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=14745134; DOI=10.1247/csf.28.419;
RA Nakatsu F., Ohno H.;
RT "Adaptor protein complexes as the key regulators of protein sorting in the
RT post-Golgi network.";
RL Cell Struct. Funct. 28:419-429(2003).
RN [11]
RP FUNCTION IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=12952941; DOI=10.1083/jcb.200305145;
RA Motley A., Bright N.A., Seaman M.N.J., Robinson M.S.;
RT "Clathrin-mediated endocytosis in AP-2-depleted cells.";
RL J. Cell Biol. 162:909-918(2003).
RN [12]
RP FUNCTION IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=12694563; DOI=10.1034/j.1600-0854.2003.00079.x;
RA Fraile-Ramos A., Kohout T.A., Waldhoer M., Marsh M.;
RT "Endocytosis of the viral chemokine receptor US28 does not require beta-
RT arrestins but is dependent on the clathrin-mediated pathway.";
RL Traffic 4:243-253(2003).
RN [13]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=15473838; DOI=10.1146/annurev.cellbio.20.010403.104543;
RA Owen D.J., Collins B.M., Evans P.R.;
RT "Adaptors for clathrin coats: structure and function.";
RL Annu. Rev. Cell Dev. Biol. 20:153-191(2004).
RN [14]
RP FUNCTION IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=14985334; DOI=10.1074/jbc.c400046200;
RA Huang F., Khvorova A., Marshall W., Sorkin A.;
RT "Analysis of clathrin-mediated endocytosis of epidermal growth factor
RT receptor by RNA interference.";
RL J. Biol. Chem. 279:16657-16661(2004).
RN [15]
RP FUNCTION IN RECEPTOR INTERNALIZATION, AND INTERACTION WITH F2R.
RX PubMed=16581796; DOI=10.1128/mcb.26.8.3231-3242.2006;
RA Paing M.M., Johnston C.A., Siderovski D.P., Trejo J.;
RT "Clathrin adaptor AP2 regulates thrombin receptor constitutive
RT internalization and endothelial cell resensitization.";
RL Mol. Cell. Biol. 26:3231-3242(2006).
RN [16]
RP INTERACTION WITH MEGF10.
RX PubMed=17643423; DOI=10.1016/j.yexcr.2007.06.015;
RA Suzuki E., Nakayama M.;
RT "MEGF10 is a mammalian ortholog of CED-1 that interacts with clathrin
RT assembly protein complex 2 medium chain and induces large vacuole
RT formation.";
RL Exp. Cell Res. 313:3729-3742(2007).
RN [17]
RP FUNCTION OF THE AP-2 COMPLEX IN NON-CLATHRIN-DEPENDENT ENDOCYTOSIS.
RX PubMed=19033387; DOI=10.1242/jcs.033522;
RA Lau A.W., Chou M.M.;
RT "The adaptor complex AP-2 regulates post-endocytic trafficking through the
RT non-clathrin Arf6-dependent endocytic pathway.";
RL J. Cell Sci. 121:4008-4017(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45 AND THR-156, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [19]
RP INTERACTION WITH KIAA0319.
RX PubMed=19419997; DOI=10.1152/ajpcell.00630.2008;
RA Levecque C., Velayos-Baeza A., Holloway Z.G., Monaco A.P.;
RT "The dyslexia-associated protein KIAA0319 interacts with adaptor protein 2
RT and follows the classical clathrin-mediated endocytosis pathway.";
RL Am. J. Physiol. 297:C160-C168(2009).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP FUNCTION, INTERACTION WITH ADAM10, AND TISSUE SPECIFICITY.
RX PubMed=23676497; DOI=10.1172/jci65401;
RA Marcello E., Saraceno C., Musardo S., Vara H., de la Fuente A.G.,
RA Pelucchi S., Di Marino D., Borroni B., Tramontano A., Perez-Otano I.,
RA Padovani A., Giustetto M., Gardoni F., Di Luca M.;
RT "Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's
RT disease.";
RL J. Clin. Invest. 123:2523-2538(2013).
RN [22]
RP INTERACTION WITH KCNQ1.
RX PubMed=23529131; DOI=10.1113/jphysiol.2013.251678;
RA Rapetti-Mauss R., O'Mahony F., Sepulveda F.V., Urbach V., Harvey B.J.;
RT "Oestrogen promotes KCNQ1 potassium channel endocytosis and postendocytic
RT trafficking in colonic epithelium.";
RL J. Physiol. (Lond.) 591:2813-2831(2013).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-156, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-156, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [26]
RP INTERACTION WITH ACE2.
RX PubMed=33436498; DOI=10.1126/scisignal.abf1117;
RA Kliche J., Kuss H., Ali M., Ivarsson Y.;
RT "Cytoplasmic short linear motifs in ACE2 and integrin beta3 link SARS-CoV-2
RT host cell receptors to mediators of endocytosis and autophagy.";
RL Sci. Signal. 14:0-0(2021).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (3.6 ANGSTROMS) OF 167-435 IN COMPLEX WITH CTLA4
RP INTERNALIZATION SIGNAL.
RX PubMed=11583591; DOI=10.1042/0264-6021:3590427;
RA Follows E.R., McPheat J.C., Minshull C., Moore N.C., Pauptit R.A.,
RA Rowsell S., Stacey C.L., Stanway J.J., Taylor I.W.F., Abbott W.M.;
RT "Study of the interaction of the medium chain mu 2 subunit of the clathrin-
RT associated adapter protein complex 2 with cytotoxic T-lymphocyte antigen 4
RT and CD28.";
RL Biochem. J. 359:427-434(2001).
RN [28]
RP VARIANT MRD60 TRP-170, CHARACTERIZATION OF VARIANT MRD60 TRP-170, FUNCTION,
RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN MRD60.
RX PubMed=31104773; DOI=10.1016/j.ajhg.2019.04.001;
RG EuroEPINOMICS-RES Consortium;
RG GRIN Consortium;
RA Helbig I., Lopez-Hernandez T., Shor O., Galer P., Ganesan S.,
RA Pendziwiat M., Rademacher A., Ellis C.A., Huempfer N., Schwarz N.,
RA Seiffert S., Peeden J., Shen J., Sterbova K., Hammer T.B., Moeller R.S.,
RA Shinde D.N., Tang S., Smith L., Poduri A., Krause R., Benninger F.,
RA Helbig K.L., Haucke V., Weber Y.G.;
RT "A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated
RT Endocytosis and Causes Developmental and Epileptic Encephalopathy.";
RL Am. J. Hum. Genet. 104:1060-1072(2019).
CC -!- FUNCTION: Component of the adaptor protein complex 2 (AP-2)
CC (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334,
CC PubMed:15473838, PubMed:31104773). Adaptor protein complexes function
CC in protein transport via transport vesicles in different membrane
CC traffic pathways (PubMed:12694563, PubMed:12952941, PubMed:14745134,
CC PubMed:14985334, PubMed:15473838, PubMed:31104773). Adaptor protein
CC complexes are vesicle coat components and appear to be involved in
CC cargo selection and vesicle formation (PubMed:12694563,
CC PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838,
CC PubMed:31104773). AP-2 is involved in clathrin-dependent endocytosis in
CC which cargo proteins are incorporated into vesicles surrounded by
CC clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion
CC with the early endosome (PubMed:12694563, PubMed:12952941,
CC PubMed:14745134, PubMed:14985334, PubMed:15473838, PubMed:31104773).
CC The clathrin lattice serves as a mechanical scaffold but is itself
CC unable to bind directly to membrane components (PubMed:12694563,
CC PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838,
CC PubMed:31104773). Clathrin-associated adaptor protein (AP) complexes
CC which can bind directly to both the clathrin lattice and to the lipid
CC and protein components of membranes are considered to be the major
CC clathrin adaptors contributing the CCV formation (PubMed:12694563,
CC PubMed:12952941, PubMed:14745134, PubMed:14985334, PubMed:15473838,
CC PubMed:31104773). AP-2 also serves as a cargo receptor to selectively
CC sort the membrane proteins involved in receptor-mediated endocytosis
CC (PubMed:16581796). AP-2 seems to play a role in the recycling of
CC synaptic vesicle membranes from the presynaptic surface
CC (PubMed:12694563, PubMed:12952941, PubMed:14745134, PubMed:14985334,
CC PubMed:15473838, PubMed:31104773). AP-2 recognizes Y-X-X-[FILMV] (Y-X-
CC X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the
CC cytosolic tails of transmembrane cargo molecules (By similarity). AP-2
CC may also play a role in maintaining normal post-endocytic trafficking
CC through the ARF6-regulated, non-clathrin pathway (PubMed:19033387).
CC During long-term potentiation in hippocampal neurons, AP-2 is
CC responsible for the endocytosis of ADAM10 (PubMed:23676497). The AP-2
CC mu subunit binds to transmembrane cargo proteins; it recognizes the Y-
CC X-X-Phi motifs (By similarity). The surface region interacting with to
CC the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes
CC accessible through a conformational change following phosphorylation of
CC AP-2 mu subunit at Thr-156 in membrane-associated AP-2
CC (PubMed:11877457). The membrane-specific phosphorylation event appears
CC to involve assembled clathrin which activates the AP-2 mu kinase AAK1
CC (PubMed:11877457). Plays a role in endocytosis of frizzled family
CC members upon Wnt signaling (By similarity).
CC {ECO:0000250|UniProtKB:P84092, ECO:0000269|PubMed:11877457,
CC ECO:0000269|PubMed:12694563, ECO:0000269|PubMed:12952941,
CC ECO:0000269|PubMed:14745134, ECO:0000269|PubMed:14985334,
CC ECO:0000269|PubMed:15473838, ECO:0000269|PubMed:16581796,
CC ECO:0000269|PubMed:19033387, ECO:0000269|PubMed:23676497,
CC ECO:0000269|PubMed:31104773}.
CC -!- SUBUNIT: Adapter protein complex 2 (AP-2) is a heterotetramer composed
CC of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type
CC subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small
CC adaptin (sigma-type subunit AP2S1) (By similarity). Interacts with
CC ATP6V1H and MEGF10 (PubMed:12032142, PubMed:17643423). Interacts with
CC EGFR and TTGN1 (By similarity). Interacts with F2R (PubMed:16581796).
CC Interacts with PIP5K1C; tyrosine phosphorylation of PIP5K1C weakens the
CC interaction (By similarity). Interacts with KIAA0319; required for
CC clathrin-mediated endocytosis of KIAA0319 (PubMed:19419997). Interacts
CC with DVL2 (via DEP domain) (By similarity). Interacts with KCNQ1;
CC mediates estrogen-induced internalization via clathrin-coated vesicles
CC (PubMed:23529131). Interacts with P2RX4 (via internalization motif) (By
CC similarity). Together with AP2A1 or AP2A2 and AP2B1, it interacts with
CC ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma
CC membrane during long-term potentiation in hippocampal neurons
CC (PubMed:23676497). Probably interacts with ACE2 (via endocytic sorting
CC signal motif); the interaction is inhibited by ACE2 phosphorylation
CC (PubMed:33436498). Interacts with RALBP1; the interaction is direct
CC (PubMed:10910768). {ECO:0000250|UniProtKB:P84091,
CC ECO:0000250|UniProtKB:P84092, ECO:0000269|PubMed:10910768,
CC ECO:0000269|PubMed:12032142, ECO:0000269|PubMed:16581796,
CC ECO:0000269|PubMed:17643423, ECO:0000269|PubMed:19419997,
CC ECO:0000269|PubMed:23529131, ECO:0000269|PubMed:23676497,
CC ECO:0000269|PubMed:33436498}.
CC -!- INTERACTION:
CC Q96CW1; Q9BYF1: ACE2; NbExp=2; IntAct=EBI-297683, EBI-7730807;
CC Q96CW1; P63010: AP2B1; NbExp=3; IntAct=EBI-297683, EBI-432924;
CC Q96CW1; Q7Z3C6: ATG9A; NbExp=8; IntAct=EBI-297683, EBI-727146;
CC Q96CW1; P0DPH9: CXorf51B; NbExp=3; IntAct=EBI-297683, EBI-23685839;
CC Q96CW1; Q96JC9: EAF1; NbExp=5; IntAct=EBI-297683, EBI-769261;
CC Q96CW1; P00533: EGFR; NbExp=5; IntAct=EBI-297683, EBI-297353;
CC Q96CW1; Q8N9N8: EIF1AD; NbExp=3; IntAct=EBI-297683, EBI-750700;
CC Q96CW1; Q86YD7: FAM90A1; NbExp=5; IntAct=EBI-297683, EBI-6658203;
CC Q96CW1; P51114: FXR1; NbExp=2; IntAct=EBI-297683, EBI-713291;
CC Q96CW1; Q99880: H2BC13; NbExp=3; IntAct=EBI-297683, EBI-1237119;
CC Q96CW1; Q16778: H2BC21; NbExp=3; IntAct=EBI-297683, EBI-1056125;
CC Q96CW1; P62807: H2BC8; NbExp=5; IntAct=EBI-297683, EBI-354552;
CC Q96CW1; Q96MH2: HEXIM2; NbExp=3; IntAct=EBI-297683, EBI-5460660;
CC Q96CW1; Q1ED39: KNOP1; NbExp=3; IntAct=EBI-297683, EBI-9977982;
CC Q96CW1; Q8N8X9: MAB21L3; NbExp=5; IntAct=EBI-297683, EBI-10268010;
CC Q96CW1; P55081: MFAP1; NbExp=3; IntAct=EBI-297683, EBI-1048159;
CC Q96CW1; Q9BU76: MMTAG2; NbExp=3; IntAct=EBI-297683, EBI-742459;
CC Q96CW1; Q00013: MPP1; NbExp=5; IntAct=EBI-297683, EBI-711788;
CC Q96CW1; Q8N3F0: MTURN; NbExp=3; IntAct=EBI-297683, EBI-11980301;
CC Q96CW1; Q9BSU3: NAA11; NbExp=3; IntAct=EBI-297683, EBI-2585120;
CC Q96CW1; Q6ZUT1: NKAPD1; NbExp=3; IntAct=EBI-297683, EBI-3920396;
CC Q96CW1; Q99633: PRPF18; NbExp=3; IntAct=EBI-297683, EBI-2798416;
CC Q96CW1; Q8NAV1: PRPF38A; NbExp=5; IntAct=EBI-297683, EBI-715374;
CC Q96CW1; Q9NZ81: PRR13; NbExp=3; IntAct=EBI-297683, EBI-740924;
CC Q96CW1; Q03393: PTS; NbExp=3; IntAct=EBI-297683, EBI-712344;
CC Q96CW1; P35268: RPL22; NbExp=3; IntAct=EBI-297683, EBI-354533;
CC Q96CW1; Q9UHP6: RSPH14; NbExp=6; IntAct=EBI-297683, EBI-748350;
CC Q96CW1; Q92609: TBC1D5; NbExp=4; IntAct=EBI-297683, EBI-742381;
CC Q96CW1; Q96EY4: TMA16; NbExp=3; IntAct=EBI-297683, EBI-1045338;
CC Q96CW1; Q68CQ4: UTP25; NbExp=5; IntAct=EBI-297683, EBI-747711;
CC Q96CW1; Q9P0T4: ZNF581; NbExp=3; IntAct=EBI-297683, EBI-745520;
CC Q96CW1; PRO_0000037566 [P27958]; Xeno; NbExp=4; IntAct=EBI-297683, EBI-6377335;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:31104773}.
CC Membrane, coated pit {ECO:0000269|PubMed:31104773}; Peripheral membrane
CC protein; Cytoplasmic side. Note=AP-2 appears to be excluded from
CC internalizing CCVs and to disengage from sites of endocytosis seconds
CC before internalization of the nascent CCV.
CC {ECO:0000250|UniProtKB:P84091}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96CW1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96CW1-2; Sequence=VSP_034599;
CC -!- TISSUE SPECIFICITY: Expressed in the brain (at protein level).
CC {ECO:0000269|PubMed:23676497}.
CC -!- PTM: Phosphorylation at Thr-156 increases the affinity of the AP-2
CC complex for cargo membrane proteins during the initial stages of
CC endocytosis. {ECO:0000269|PubMed:11877457}.
CC -!- DISEASE: Intellectual developmental disorder, autosomal dominant 60,
CC with seizures (MRD60) [MIM:618587]: An autosomal dominant disorder
CC characterized by global developmental delay apparent in the first six
CC months of life, followed by onset of seizures between 21 months and 4
CC years. Disease features include moderate-to-severe intellectual
CC disability, poor speech, delayed walking, and ataxia.
CC {ECO:0000269|PubMed:31104773}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the adaptor complexes medium subunit family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA09762.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U36188; AAA93254.1; -; mRNA.
DR EMBL; D63475; BAA09762.2; ALT_INIT; mRNA.
DR EMBL; BT007308; AAP35972.1; -; mRNA.
DR EMBL; AC131235; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78290.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78291.1; -; Genomic_DNA.
DR EMBL; BC004996; AAH04996.1; -; mRNA.
DR EMBL; BC013796; AAH13796.1; -; mRNA.
DR EMBL; BC014030; AAH14030.1; -; mRNA.
DR CCDS; CCDS43177.1; -. [Q96CW1-1]
DR CCDS; CCDS43178.1; -. [Q96CW1-2]
DR PIR; G02088; G02088.
DR RefSeq; NP_001020376.1; NM_001025205.1. [Q96CW1-2]
DR RefSeq; NP_001298127.1; NM_001311198.1.
DR RefSeq; NP_004059.2; NM_004068.3. [Q96CW1-1]
DR PDB; 1H6E; X-ray; 3.60 A; A=164-435.
DR PDB; 6BNT; X-ray; 3.20 A; A=160-435.
DR PDB; 6URI; X-ray; 3.00 A; M=1-135.
DR PDBsum; 1H6E; -.
DR PDBsum; 6BNT; -.
DR PDBsum; 6URI; -.
DR AlphaFoldDB; Q96CW1; -.
DR SMR; Q96CW1; -.
DR BioGRID; 107587; 391.
DR ComplexPortal; CPX-5149; AP-2 Adaptor complex, alpha1 variant.
DR ComplexPortal; CPX-5150; AP-2 Adaptor complex, alpha2 variant.
DR CORUM; Q96CW1; -.
DR IntAct; Q96CW1; 210.
DR MINT; Q96CW1; -.
DR STRING; 9606.ENSP00000292807; -.
DR TCDB; 9.B.278.1.4; the organellar-targeting adaptor protein complex (o-apc) family.
DR GlyGen; Q96CW1; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96CW1; -.
DR MetOSite; Q96CW1; -.
DR PhosphoSitePlus; Q96CW1; -.
DR SwissPalm; Q96CW1; -.
DR BioMuta; AP2M1; -.
DR DMDM; 51316978; -.
DR EPD; Q96CW1; -.
DR jPOST; Q96CW1; -.
DR MassIVE; Q96CW1; -.
DR MaxQB; Q96CW1; -.
DR PaxDb; Q96CW1; -.
DR PeptideAtlas; Q96CW1; -.
DR PRIDE; Q96CW1; -.
DR ProteomicsDB; 76229; -. [Q96CW1-1]
DR ProteomicsDB; 76230; -. [Q96CW1-2]
DR Antibodypedia; 33793; 569 antibodies from 35 providers.
DR DNASU; 1173; -.
DR Ensembl; ENST00000292807.9; ENSP00000292807.5; ENSG00000161203.14. [Q96CW1-1]
DR Ensembl; ENST00000382456.7; ENSP00000371894.3; ENSG00000161203.14. [Q96CW1-2]
DR Ensembl; ENST00000439647.5; ENSP00000409081.1; ENSG00000161203.14. [Q96CW1-2]
DR Ensembl; ENST00000621863.5; ENSP00000481563.2; ENSG00000161203.14. [Q96CW1-2]
DR GeneID; 1173; -.
DR KEGG; hsa:1173; -.
DR MANE-Select; ENST00000292807.9; ENSP00000292807.5; NM_004068.4; NP_004059.2.
DR UCSC; uc003fmw.4; human. [Q96CW1-1]
DR CTD; 1173; -.
DR DisGeNET; 1173; -.
DR GeneCards; AP2M1; -.
DR HGNC; HGNC:564; AP2M1.
DR HPA; ENSG00000161203; Low tissue specificity.
DR MalaCards; AP2M1; -.
DR MIM; 601024; gene.
DR MIM; 618587; phenotype.
DR neXtProt; NX_Q96CW1; -.
DR OpenTargets; ENSG00000161203; -.
DR Orphanet; 1942; Myoclonic-astatic epilepsy.
DR PharmGKB; PA24855; -.
DR VEuPathDB; HostDB:ENSG00000161203; -.
DR eggNOG; KOG0938; Eukaryota.
DR GeneTree; ENSGT00940000159223; -.
DR HOGENOM; CLU_026996_5_2_1; -.
DR InParanoid; Q96CW1; -.
DR OMA; VWKIPRI; -.
DR OrthoDB; 725236at2759; -.
DR PhylomeDB; Q96CW1; -.
DR TreeFam; TF300722; -.
DR PathwayCommons; Q96CW1; -.
DR Reactome; R-HSA-164939; Nef mediated downregulation of CD28 cell surface expression.
DR Reactome; R-HSA-167590; Nef Mediated CD4 Down-regulation.
DR Reactome; R-HSA-177504; Retrograde neurotrophin signalling.
DR Reactome; R-HSA-182218; Nef Mediated CD8 Down-regulation.
DR Reactome; R-HSA-190873; Gap junction degradation.
DR Reactome; R-HSA-196025; Formation of annular gap junctions.
DR Reactome; R-HSA-2132295; MHC class II antigen presentation.
DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells.
DR Reactome; R-HSA-416993; Trafficking of GluR2-containing AMPA receptors. [Q96CW1-2]
DR Reactome; R-HSA-437239; Recycling pathway of L1.
DR Reactome; R-HSA-5099900; WNT5A-dependent internalization of FZD4.
DR Reactome; R-HSA-5140745; WNT5A-dependent internalization of FZD2, FZD5 and ROR2.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-HSA-8866427; VLDLR internalisation and degradation.
DR Reactome; R-HSA-8964038; LDL clearance.
DR Reactome; R-HSA-9679191; Potential therapeutics for SARS.
DR SignaLink; Q96CW1; -.
DR SIGNOR; Q96CW1; -.
DR BioGRID-ORCS; 1173; 556 hits in 1098 CRISPR screens.
DR ChiTaRS; AP2M1; human.
DR EvolutionaryTrace; Q96CW1; -.
DR GeneWiki; AP2M1; -.
DR GenomeRNAi; 1173; -.
DR Pharos; Q96CW1; Tbio.
DR PRO; PR:Q96CW1; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q96CW1; protein.
DR Bgee; ENSG00000161203; Expressed in right frontal lobe and 205 other tissues.
DR ExpressionAtlas; Q96CW1; baseline and differential.
DR Genevisible; Q96CW1; HS.
DR GO; GO:0030122; C:AP-2 adaptor complex; IDA:UniProtKB.
DR GO; GO:0045334; C:clathrin-coated endocytic vesicle; NAS:ARUK-UCL.
DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0005905; C:clathrin-coated pit; IDA:UniProtKB.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IC:ComplexPortal.
DR GO; GO:0031410; C:cytoplasmic vesicle; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0036020; C:endolysosome membrane; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0098794; C:postsynapse; IEA:GOC.
DR GO; GO:0098793; C:presynapse; IEA:GOC.
DR GO; GO:0035615; F:clathrin adaptor activity; IBA:GO_Central.
DR GO; GO:0097718; F:disordered domain specific binding; IEA:Ensembl.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISS:BHF-UCL.
DR GO; GO:0005048; F:signal sequence binding; IDA:BHF-UCL.
DR GO; GO:0044325; F:transmembrane transporter binding; IPI:UniProtKB.
DR GO; GO:0072583; P:clathrin-dependent endocytosis; IDA:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IBA:GO_Central.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:1903077; P:negative regulation of protein localization to plasma membrane; IMP:UniProtKB.
DR GO; GO:0002092; P:positive regulation of receptor internalization; IEA:Ensembl.
DR GO; GO:1900244; P:positive regulation of synaptic vesicle endocytosis; IEA:Ensembl.
DR GO; GO:0098884; P:postsynaptic neurotransmitter receptor internalization; IC:ComplexPortal.
DR GO; GO:0065003; P:protein-containing complex assembly; TAS:GO_Central.
DR GO; GO:0031623; P:receptor internalization; IMP:ARUK-UCL.
DR GO; GO:0097494; P:regulation of vesicle size; IMP:ARUK-UCL.
DR GO; GO:0048488; P:synaptic vesicle endocytosis; IEA:Ensembl.
DR GO; GO:0006900; P:vesicle budding from membrane; IMP:ARUK-UCL.
DR GO; GO:0016192; P:vesicle-mediated transport; IBA:GO_Central.
DR CDD; cd09251; AP-2_Mu2_Cterm; 1.
DR CDD; cd14836; AP2_Mu_N; 1.
DR InterPro; IPR036168; AP2_Mu_C_sf.
DR InterPro; IPR043532; AP2_Mu_N.
DR InterPro; IPR022775; AP_mu_sigma_su.
DR InterPro; IPR001392; Clathrin_mu.
DR InterPro; IPR018240; Clathrin_mu_CS.
DR InterPro; IPR011012; Longin-like_dom_sf.
DR InterPro; IPR028565; MHD.
DR InterPro; IPR043512; Mu2_C.
DR Pfam; PF00928; Adap_comp_sub; 1.
DR Pfam; PF01217; Clat_adaptor_s; 1.
DR PIRSF; PIRSF005992; Clathrin_mu; 1.
DR PRINTS; PR00314; CLATHRINADPT.
DR SUPFAM; SSF49447; SSF49447; 1.
DR SUPFAM; SSF64356; SSF64356; 1.
DR PROSITE; PS00990; CLAT_ADAPTOR_M_1; 1.
DR PROSITE; PS00991; CLAT_ADAPTOR_M_2; 1.
DR PROSITE; PS51072; MHD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Coated pit;
KW Disease variant; Endocytosis; Epilepsy; Intellectual disability;
KW Lipid-binding; Membrane; Phosphoprotein; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1..435
FT /note="AP-2 complex subunit mu"
FT /id="PRO_0000193774"
FT DOMAIN 170..434
FT /note="MHD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00404"
FT BINDING 341
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
FT inositol-3,4,5-trisphosphate)"
FT /ligand_id="ChEBI:CHEBI:57836"
FT /evidence="ECO:0000250|UniProtKB:P84092"
FT BINDING 345
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
FT inositol-3,4,5-trisphosphate)"
FT /ligand_id="ChEBI:CHEBI:57836"
FT /evidence="ECO:0000250|UniProtKB:P84092"
FT BINDING 354
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
FT inositol-3,4,5-trisphosphate)"
FT /ligand_id="ChEBI:CHEBI:57836"
FT /evidence="ECO:0000250|UniProtKB:P84092"
FT MOD_RES 45
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 156
FT /note="Phosphothreonine; by AAK1"
FT /evidence="ECO:0000269|PubMed:11877457,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT VAR_SEQ 141..142
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_034599"
FT VARIANT 170
FT /note="R -> W (in MRD60; reduced clathrin-mediated
FT endocytosis; no effect on clathrin-coated pit location; no
FT effect on protein stability and membrane recruitment;
FT dbSNP:rs1577059692)"
FT /evidence="ECO:0000269|PubMed:31104773"
FT /id="VAR_082954"
FT CONFLICT 106
FT /note="V -> L (in Ref. 1; AAA93254)"
FT /evidence="ECO:0000305"
FT STRAND 4..8
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 14..22
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 28..35
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 45..50
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 53..60
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 63..71
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 75..93
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 98..103
FT /evidence="ECO:0007829|PDB:6URI"
FT HELIX 106..115
FT /evidence="ECO:0007829|PDB:6URI"
FT STRAND 172..185
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 191..205
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 207..209
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 211..216
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 245..248
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 263..265
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 269..279
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 287..296
FT /evidence="ECO:0007829|PDB:6BNT"
FT TURN 297..299
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 300..309
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 315..325
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 330..345
FT /evidence="ECO:0007829|PDB:6BNT"
FT TURN 346..349
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 350..372
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 386..394
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 401..407
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 409..412
FT /evidence="ECO:0007829|PDB:6BNT"
FT HELIX 415..417
FT /evidence="ECO:0007829|PDB:6BNT"
FT STRAND 418..433
FT /evidence="ECO:0007829|PDB:6BNT"
SQ SEQUENCE 435 AA; 49655 MW; 82803219BA279954 CRC64;
MIGGLFIYNH KGEVLISRVY RDDIGRNAVD AFRVNVIHAR QQVRSPVTNI ARTSFFHVKR
SNIWLAAVTK QNVNAAMVFE FLYKMCDVMA AYFGKISEEN IKNNFVLIYE LLDEILDFGY
PQNSETGALK TFITQQGIKS QHQTKEEQSQ ITSQVTGQIG WRREGIKYRR NELFLDVLES
VNLLMSPQGQ VLSAHVSGRV VMKSYLSGMP ECKFGMNDKI VIEKQGKGTA DETSKSGKQS
IAIDDCTFHQ CVRLSKFDSE RSISFIPPDG EFELMRYRTT KDIILPFRVI PLVREVGRTK
LEVKVVIKSN FKPSLLAQKI EVRIPTPLNT SGVQVICMKG KAKYKASENA IVWKIKRMAG
MKESQISAEI ELLPTNDKKK WARPPISMNF EVPFAPSGLK VRYLKVFEPK LNYSDHDVIK
WVRYIGRSGI YETRC
