AMRA1_HUMAN
ID AMRA1_HUMAN Reviewed; 1298 AA.
AC Q9C0C7; A6XN33; D3DQP8; G3V193; Q86XD6; Q9H8Z0; Q9NXE7;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 15-JAN-2008, sequence version 2.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Activating molecule in BECN1-regulated autophagy protein 1 {ECO:0000303|PubMed:17589504};
DE AltName: Full=DDB1- and CUL4-associated factor 3 {ECO:0000303|PubMed:16949367};
GN Name=AMBRA1 {ECO:0000303|PubMed:17589504, ECO:0000312|HGNC:HGNC:25990};
GN Synonyms=DCAF3 {ECO:0000303|PubMed:16949367},
GN KIAA1736 {ECO:0000303|PubMed:11214970};
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 3).
RC TISSUE=Brain;
RX PubMed=17589504; DOI=10.1038/nature05925;
RA Maria Fimia G., Stoykova A., Romagnoli A., Giunta L., Di Bartolomeo S.,
RA Nardacci R., Corazzari M., Fuoco C., Ucar A., Schwartz P., Gruss P.,
RA Piacentini M., Chowdhury K., Cecconi F.;
RT "Ambra1 regulates autophagy and development of the nervous system.";
RL Nature 447:1121-1125(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=11214970; DOI=10.1093/dnares/7.6.347;
RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIX. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:347-355(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 464-1298.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Testis;
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 [8]
RP IDENTIFICATION IN A DCX (DDB1-CUL4-X-BOX) E3 UBIQUITIN-PROTEIN LIGASE
RP COMPLEX.
RX PubMed=16949367; DOI=10.1016/j.molcel.2006.08.010;
RA Jin J., Arias E.E., Chen J., Harper J.W., Walter J.C.;
RT "A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is
RT required for S phase destruction of the replication factor Cdt1.";
RL Mol. Cell 23:709-721(2006).
RN [9]
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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH DYNLL1 AND DYNLL2, AND
RP MUTAGENESIS OF GLN-1105 AND GLN-1117.
RX PubMed=20921139; DOI=10.1083/jcb.201002100;
RA Di Bartolomeo S., Corazzari M., Nazio F., Oliverio S., Lisi G.,
RA Antonioli M., Pagliarini V., Matteoni S., Fuoco C., Giunta L., D'Amelio M.,
RA Nardacci R., Romagnoli A., Piacentini M., Cecconi F., Fimia G.M.;
RT "The dynamic interaction of AMBRA1 with the dynein motor complex regulates
RT mammalian autophagy.";
RL J. Cell Biol. 191:155-168(2010).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
RP FUNCTION, INTERACTION WITH BCL2 AND BECN1, AND SUBCELLULAR LOCATION.
RX PubMed=21358617; DOI=10.1038/emboj.2011.49;
RA Strappazzon F., Vietri-Rudan M., Campello S., Nazio F., Florenzano F.,
RA Fimia G.M., Piacentini M., Levine B., Cecconi F.;
RT "Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy.";
RL EMBO J. 30:1195-1208(2011).
RN [15]
RP FUNCTION.
RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011;
RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K.,
RA De Strooper B., Vandenberghe W.;
RT "Parkin interacts with Ambra1 to induce mitophagy.";
RL J. Neurosci. 31:10249-10261(2011).
RN [16]
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-482.
RX PubMed=22441670; DOI=10.1038/cdd.2012.27;
RA Pagliarini V., Wirawan E., Romagnoli A., Ciccosanti F., Lisi G.,
RA Lippens S., Cecconi F., Fimia G.M., Vandenabeele P., Corazzari M.,
RA Piacentini M.;
RT "Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the
RT autophagic pro-survival response.";
RL Cell Death Differ. 19:1495-1504(2012).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [18]
RP INTERACTION WITH BECN2.
RX PubMed=23954414; DOI=10.1016/j.cell.2013.07.035;
RA He C., Wei Y., Sun K., Li B., Dong X., Zou Z., Liu Y., Kinch L.N., Khan S.,
RA Sinha S., Xavier R.J., Grishin N.V., Xiao G., Eskelinen E.L., Scherer P.E.,
RA Whistler J.L., Levine B.;
RT "Beclin 2 functions in autophagy, degradation of G protein-coupled
RT receptors, and metabolism.";
RL Cell 154:1085-1099(2013).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-328; SER-394; SER-443;
RP SER-635; SER-639 AND SER-1205, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [20]
RP FUNCTION, PATHWAY, INTERACTION WITH TRAF6, PHOSPHORYLATION AT SER-52, AND
RP MUTAGENESIS OF SER-52; GLU-620; GLU-642; GLU-682; GLU-918 AND GLU-1134.
RX PubMed=23524951; DOI=10.1038/ncb2708;
RA Nazio F., Strappazzon F., Antonioli M., Bielli P., Cianfanelli V.,
RA Bordi M., Gretzmeier C., Dengjel J., Piacentini M., Fimia G.M., Cecconi F.;
RT "mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-
RT association and function through AMBRA1 and TRAF6.";
RL Nat. Cell Biol. 15:406-416(2013).
RN [21]
RP FUNCTION, UBIQUITINATION, INTERACTION WITH CUL4 AND DDB1, AND MUTAGENESIS
RP OF SER-52.
RX PubMed=25499913; DOI=10.1016/j.devcel.2014.11.013;
RA Antonioli M., Albiero F., Nazio F., Vescovo T., Perdomo A.B., Corazzari M.,
RA Marsella C., Piselli P., Gretzmeier C., Dengjel J., Cecconi F.,
RA Piacentini M., Fimia G.M.;
RT "AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy
RT dynamics.";
RL Dev. Cell 31:734-746(2014).
RN [22]
RP IDENTIFICATION BY 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 [23]
RP FUNCTION.
RX PubMed=24587252; DOI=10.1371/journal.pone.0090151;
RA Gu W., Wan D., Qian Q., Yi B., He Z., Gu Y., Wang L., He S.;
RT "Ambra1 is an essential regulator of autophagy and apoptosis in SW620
RT cells: pro-survival role of Ambra1.";
RL PLoS ONE 9:e90151-e90151(2014).
RN [24]
RP FUNCTION, AND INTERACTION WITH PPP2CA AND BECN1.
RX PubMed=25803737; DOI=10.1080/15384101.2015.1021526;
RA Cianfanelli V., D'Orazio M., Cecconi F.;
RT "AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell
RT proliferation.";
RL Cell Cycle 14:959-963(2015).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, INTERACTION WITH MAP1LC3B, AND
RP MUTAGENESIS OF 1049-TRP--LEU-1052.
RX PubMed=25215947; DOI=10.1038/cdd.2014.139;
RA Strappazzon F., Nazio F., Corrado M., Cianfanelli V., Romagnoli A.,
RA Fimia G.M., Campello S., Nardacci R., Piacentini M., Campanella M.,
RA Cecconi F.;
RT "AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN
RT and p62/SQSTM1.";
RL Cell Death Differ. 22:419-432(2015).
RN [26]
RP FUNCTION, INTERACTION WITH BECN1; PPP2CA AND ULK1, PXP MOTIF, DOMAIN,
RP PHOSPHORYLATION, AND MUTAGENESIS OF 275-PRO--PRO-277 AND
RP 1206-PRO--PRO-1208.
RX PubMed=25438055; DOI=10.1038/ncb3072;
RA Cianfanelli V., Fuoco C., Lorente M., Salazar M., Quondamatteo F.,
RA Gherardini P.F., De Zio D., Nazio F., Antonioli M., D'Orazio M., Skobo T.,
RA Bordi M., Rohde M., Dalla Valle L., Helmer-Citterich M., Gretzmeier C.,
RA Dengjel J., Fimia G.M., Piacentini M., Di Bartolomeo S., Velasco G.,
RA Cecconi F.;
RT "AMBRA1 links autophagy to cell proliferation and tumorigenesis by
RT promoting c-Myc dephosphorylation and degradation.";
RL Nat. Cell Biol. 17:20-30(2015).
RN [27]
RP INDUCTION.
RX PubMed=28059583; DOI=10.1080/15548627.2016.1269989;
RA Capizzi M., Strappazzon F., Cianfanelli V., Papaleo E., Cecconi F.;
RT "MIR7-3HG, a MYC-dependent modulator of cell proliferation, inhibits
RT autophagy by a regulatory loop involving AMBRA1.";
RL Autophagy 13:554-566(2017).
RN [28]
RP FUNCTION, INTERACTION WITH PPP2CA, DOMAIN, INDUCTION, AND MUTAGENESIS OF
RP 275-PRO--PRO-277 AND 1206-PRO--PRO-1208.
RX PubMed=30513302; DOI=10.1016/j.devcel.2018.11.010;
RA Becher J., Simula L., Volpe E., Procaccini C., La Rocca C., D'Acunzo P.,
RA Cianfanelli V., Strappazzon F., Caruana I., Nazio F., Weber G.,
RA Gigantino V., Botti G., Ciccosanti F., Borsellino G., Campello S.,
RA Mandolesi G., De Bardi M., Fimia G.M., D'Amelio M., Ruffini F., Furlan R.,
RA Centonze D., Martino G., Braghetta P., Chrisam M., Bonaldo P., Matarese G.,
RA Locatelli F., Battistini L., Cecconi F.;
RT "AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream
RT of the FOXO3-FOXP3 axis.";
RL Dev. Cell 47:592-607(2018).
RN [29]
RP FUNCTION, IDENTIFICATION IN A DCX (DDB1-CUL4-X-BOX) E3 UBIQUITIN-PROTEIN
RP LIGASE COMPLEX, PATHWAY, INTERACTION WITH DDB1, AND MUTAGENESIS OF
RP 1-MET--ALA-22 AND 1-MET--GLU-43.
RX PubMed=30166453; DOI=10.15252/embj.201797508;
RA Chen S.H., Jang G.M., Huettenhain R., Gordon D.E., Du D., Newton B.W.,
RA Johnson J.R., Hiatt J., Hultquist J.F., Johnson T.L., Liu Y.L.,
RA Burton L.A., Ye J., Reichermeier K.M., Stroud R.M., Marson A., Debnath J.,
RA Gross J.D., Krogan N.J.;
RT "CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to
RT modulate CRL5 signaling.";
RL EMBO J. 37:0-0(2018).
RN [30]
RP FUNCTION, INTERACTION WITH HUWE1, DOMAIN, INTERACTION WITH GABARAP AND
RP MAP1LC3B, PHOSPHORYLATION AT SER-1043, AND MUTAGENESIS OF SER-1043.
RX PubMed=30217973; DOI=10.1038/s41467-018-05722-3;
RA Di Rita A., Peschiaroli A., D'Acunzo P., Strobbe D., Hu Z., Gruber J.,
RA Nygaard M., Lambrughi M., Melino G., Papaleo E., Dengjel J., El Alaoui S.,
RA Campanella M., Doetsch V., Rogov V.V., Strappazzon F., Cecconi F.;
RT "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating
RT AMBRA1 activation via IKKalpha.";
RL Nat. Commun. 9:3755-3755(2018).
RN [31]
RP FUNCTION, AND INTERACTION WITH TRIM32.
RX PubMed=31123703; DOI=10.1126/sciadv.aau8857;
RA Di Rienzo M., Antonioli M., Fusco C., Liu Y., Mari M., Orhon I., Refolo G.,
RA Germani F., Corazzari M., Romagnoli A., Ciccosanti F., Mandriani B.,
RA Pellico M.T., De La Torre R., Ding H., Dentice M., Neri M., Ferlini A.,
RA Reggiori F., Kulesz-Martin M., Piacentini M., Merla G., Fimia G.M.;
RT "Autophagy induction in atrophic muscle cells requires ULK1 activation by
RT TRIM32 through unanchored K63-linked polyubiquitin chains.";
RL Sci. Adv. 5:eaau8857-eaau8857(2019).
RN [32]
RP SUBCELLULAR LOCATION.
RX PubMed=32616651; DOI=10.1074/jbc.ra120.012565;
RA Schoenherr C., Byron A., Griffith B., Loftus A., Wills J.C., Munro A.F.,
RA von Kriegsheim A., Frame M.C.;
RT "The autophagy protein Ambra1 regulates gene expression by supporting novel
RT transcriptional complexes.";
RL J. Biol. Chem. 295:12045-12057(2020).
RN [33]
RP FUNCTION, IDENTIFICATION IN A DCX (DDB1-CUL4-X-BOX) E3 UBIQUITIN-PROTEIN
RP LIGASE COMPLEX, AND PATHWAY.
RX PubMed=33854232; DOI=10.1038/s41586-021-03422-5;
RA Maiani E., Milletti G., Nazio F., Holdgaard S.G., Bartkova J., Rizza S.,
RA Cianfanelli V., Lorente M., Simoneschi D., Di Marco M., D'Acunzo P.,
RA Di Leo L., Rasmussen R., Montagna C., Raciti M., De Stefanis C.,
RA Gabicagogeascoa E., Rona G., Salvador N., Pupo E., Merchut-Maya J.M.,
RA Daniel C.J., Carinci M., Cesarini V., O'sullivan A., Jeong Y.T., Bordi M.,
RA Russo F., Campello S., Gallo A., Filomeni G., Lanzetti L., Sears R.C.,
RA Hamerlik P., Bartolazzi A., Hynds R.E., Pearce D.R., Swanton C., Pagano M.,
RA Velasco G., Papaleo E., De Zio D., Maya-Mendoza A., Locatelli F.,
RA Bartek J., Cecconi F.;
RT "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.";
RL Nature 592:799-803(2021).
RN [34]
RP FUNCTION, AND PATHWAY.
RX PubMed=33854235; DOI=10.1038/s41586-021-03445-y;
RA Simoneschi D., Rona G., Zhou N., Jeong Y.T., Jiang S., Milletti G.,
RA Arbini A.A., O'Sullivan A., Wang A.A., Nithikasem S., Keegan S., Siu Y.,
RA Cianfanelli V., Maiani E., Nazio F., Cecconi F., Boccalatte F., Fenyoe D.,
RA Jones D.R., Busino L., Pagano M.;
RT "CRL4AMBRA1 is a master regulator of D-type cyclins.";
RL Nature 592:789-793(2021).
RN [35]
RP FUNCTION, IDENTIFICATION IN A DCX (DDB1-CUL4-X-BOX) E3 UBIQUITIN-PROTEIN
RP LIGASE COMPLEX, AND PATHWAY.
RX PubMed=33854239; DOI=10.1038/s41586-021-03474-7;
RA Chaikovsky A.C., Li C., Jeng E.E., Loebell S., Lee M.C., Murray C.W.,
RA Cheng R., Demeter J., Swaney D.L., Chen S.H., Newton B.W., Johnson J.R.,
RA Drainas A.P., Shue Y.T., Seoane J.A., Srinivasan P., He A., Yoshida A.,
RA Hipkins S.Q., McCrea E., Poltorack C.D., Krogan N.J., Diehl J.A., Kong C.,
RA Jackson P.K., Curtis C., Petrov D.A., Bassik M.C., Winslow M.M., Sage J.;
RT "The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D.";
RL Nature 592:794-798(2021).
RN [36]
RP VARIANTS MET-80; PHE-364; PHE-833; VAL-974 AND PHE-1043, CHARACTERIZATION
RP OF VARIANTS MET-80; PHE-364; PHE-833; VAL-974 AND PHE-1043, AND FUNCTION.
RX PubMed=32333458; DOI=10.1002/humu.24028;
RA Ye J., Tong Y., Lv J., Peng R., Chen S., Kuang L., Su K., Zheng Y.,
RA Zhang T., Zhang F., Jin L., Yang X., Wang H.;
RT "Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human
RT neural tube defects.";
RL Hum. Mutat. 41:1383-1393(2020).
CC -!- FUNCTION: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3
CC ubiquitin-protein ligase complex involved in cell cycle control and
CC autophagy (PubMed:20921139, PubMed:23524951, PubMed:24587252,
CC PubMed:33854232, PubMed:33854235, PubMed:33854239, PubMed:32333458).
CC The DCX(AMBRA1) complex specifically mediates the polyubiquitination of
CC target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1
CC (PubMed:23524951, PubMed:33854232, PubMed:33854235, PubMed:33854239).
CC Acts as an upstream master regulator of the transition from G1 to S
CC cell phase: AMBRA1 specifically recognizes and binds phosphorylated
CC cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination
CC by the DCX(AMBRA1) complex and subsequent degradation (PubMed:33854232,
CC PubMed:33854235, PubMed:33854239). By controlling the transition from
CC G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor
CC suppressor that promotes genomic integrity during DNA replication and
CC counteracts developmental abnormalities and tumor growth
CC (PubMed:33854232, PubMed:33854235, PubMed:33854239). AMBRA1 also
CC regulates the cell cycle by promoting MYC dephosphorylation and
CC degradation independently of the DCX(AMBRA1) complex: acts via
CC interaction with the catalytic subunit of protein phosphatase 2A
CC (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to
CC MYC dephosphorylation and degradation (PubMed:25803737,
CC PubMed:25438055). Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-
CC protein ligase complexes by mediating ubiquitination and degradation of
CC Elongin-C (ELOC) component of CRL5 complexes (PubMed:25499913,
CC PubMed:30166453). Acts as a key regulator of autophagy by modulating
CC the BECN1-PIK3C3 complex: controls protein turnover during neuronal
CC development, and regulates normal cell survival and proliferation
CC (PubMed:21358617). In normal conditions, AMBRA1 is tethered to the
CC cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2
CC (PubMed:20921139). Upon autophagy induction, AMBRA1 is released from
CC the cytoskeletal docking site to induce autophagosome nucleation by
CC mediating ubiquitination of proteins involved in autophagy
CC (PubMed:20921139). The DCX(AMBRA1) complex mediates 'Lys-63'-linked
CC ubiquitination of BECN1, increasing the association between BECN1 and
CC PIK3C3 to promote PIK3C3 activity (By similarity). In collaboration
CC with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1
CC following autophagy induction, promoting ULK1 stability and kinase
CC activity (PubMed:23524951). Also activates ULK1 via interaction with
CC TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked
CC polyubiquitin chains (PubMed:31123703). Also acts as an activator of
CC mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A,
CC MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto
CC autophagosomes (PubMed:21753002, PubMed:25215947). Also activates
CC mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-
CC mediated ubiquitination of MFN2 (PubMed:30217973). AMBRA1 is also
CC involved in regulatory T-cells (Treg) differentiation by promoting
CC FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts
CC via interaction with PPP2CA, which enhances interaction between PPP2CA
CC and FOXO3, leading to FOXO3 dephosphorylation and stabilization
CC (PubMed:30513302). May act as a regulator of intracellular trafficking,
CC regulating the localization of active PTK2/FAK and SRC (By similarity).
CC Also involved in transcription regulation by acting as a scaffold for
CC protein complexes at chromatin (By similarity).
CC {ECO:0000250|UniProtKB:A2AH22, ECO:0000269|PubMed:20921139,
CC ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:21753002,
CC ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:24587252,
CC ECO:0000269|PubMed:25215947, ECO:0000269|PubMed:25438055,
CC ECO:0000269|PubMed:25499913, ECO:0000269|PubMed:25803737,
CC ECO:0000269|PubMed:30166453, ECO:0000269|PubMed:30217973,
CC ECO:0000269|PubMed:30513302, ECO:0000269|PubMed:31123703,
CC ECO:0000269|PubMed:32333458, ECO:0000269|PubMed:33854232,
CC ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:30166453,
CC ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235,
CC ECO:0000269|PubMed:33854239}.
CC -!- SUBUNIT: Component of the DCX(AMBRA1) E3 ubiquitin ligase complex, also
CC named CRL4(AMBRA1), at least composed of CUL4 (CUL4A or CUL4B), DDB1,
CC AMBRA1 and RBX1 (PubMed:25499913, PubMed:16949367, PubMed:30166453,
CC PubMed:33854232, PubMed:33854239). Interacts with BECN1
CC (PubMed:21358617, PubMed:25438055). Probably forms a complex with BECN1
CC and PIK3C3 (By similarity). Interacts with BECN2 (PubMed:23954414).
CC Interacts with BCL2; leading to prevent interaction with BCN1 and
CC autophagy, interaction is disrupted upon autophagy induction
CC (PubMed:21358617). Interacts with ULK1 (PubMed:25438055). Interacts
CC (via PxP motifs) with PPP2CA; enhancing interaction between PPP2CA and
CC MYC or FOXO3 (PubMed:25438055, PubMed:30513302). Forms a complex with
CC PPP2CA and BECN1; AMBRA1 and BECN1 components of the complex regulate
CC MYC stability via different pathways (PubMed:25803737). Interacts (TQT
CC motifs) with DYNLL1 and DYNLL2; tethering AMBRA1 and the BECN1-PIK3C3
CC complex in absence of autophagy (PubMed:20921139). Interacts with
CC TRAF6; interaction is required to mediate 'Lys-63'-linked
CC ubiquitination of ULK1 (PubMed:23524951). Interacts with TRIM32;
CC promoting activation of ULK1 by TRIM32 via unanchored 'Lys-63'-linked
CC polyubiquitin chains (PubMed:31123703). Interacts with PRKN (By
CC similarity). Interacts (via LIR motif) with LC3 (MAP1LC3A, MAP1LC3B or
CC MAP1LC3C) (PubMed:25215947, PubMed:30217973). Interacts with HUWE1
CC (PubMed:30217973). Interacts with PTK2/FAK (By similarity). Interacts
CC with SRC; required for SRC trafficking to autophagosomes (By
CC similarity). {ECO:0000250|UniProtKB:A2AH22,
CC ECO:0000269|PubMed:16949367, ECO:0000269|PubMed:20921139,
CC ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:23524951,
CC ECO:0000269|PubMed:23954414, ECO:0000269|PubMed:25215947,
CC ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:25499913,
CC ECO:0000269|PubMed:25803737, ECO:0000269|PubMed:30166453,
CC ECO:0000269|PubMed:30217973, ECO:0000269|PubMed:30513302,
CC ECO:0000269|PubMed:31123703, ECO:0000269|PubMed:33854232,
CC ECO:0000269|PubMed:33854239}.
CC -!- INTERACTION:
CC Q9C0C7; P10415: BCL2; NbExp=10; IntAct=EBI-2512975, EBI-77694;
CC Q9C0C7; Q14457: BECN1; NbExp=9; IntAct=EBI-2512975, EBI-949378;
CC Q9C0C7; P30153: PPP2R1A; NbExp=3; IntAct=EBI-2512975, EBI-302388;
CC Q9C0C7; O75385: ULK1; NbExp=3; IntAct=EBI-2512975, EBI-908831;
CC Q9C0C7; P12504: vif; Xeno; NbExp=5; IntAct=EBI-2512975, EBI-779991;
CC Q9C0C7-3; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-16042318, EBI-359276;
CC Q9C0C7-3; O75385: ULK1; NbExp=4; IntAct=EBI-16042318, EBI-908831;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000269|PubMed:20921139}. Cytoplasm, cytoskeleton
CC {ECO:0000269|PubMed:20921139}. Cytoplasmic vesicle, autophagosome
CC {ECO:0000250|UniProtKB:A2AH22}. Mitochondrion
CC {ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:25215947}. Cytoplasm,
CC cytosol {ECO:0000250|UniProtKB:A2AH22}. Nucleus
CC {ECO:0000269|PubMed:32616651}. Cell junction, focal adhesion
CC {ECO:0000250|UniProtKB:A2AH22}. Note=Localizes to the cytoskeleton in
CC absence of autophagy induction (PubMed:20921139). Upon autophagy
CC induction, AMBRA1 relocalizes to the endoplasmic reticulum to enable
CC autophagosome nucleation (PubMed:20921139). Partially localizes at
CC mitochondria in normal conditions (PubMed:21358617). Localizes also to
CC discrete punctae along the ciliary axoneme (By similarity).
CC {ECO:0000250|UniProtKB:A2AH22, ECO:0000269|PubMed:20921139,
CC ECO:0000269|PubMed:21358617}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=Q9C0C7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9C0C7-2; Sequence=VSP_030657;
CC Name=3;
CC IsoId=Q9C0C7-3; Sequence=VSP_030655;
CC Name=4;
CC IsoId=Q9C0C7-4; Sequence=VSP_030654;
CC Name=5;
CC IsoId=Q9C0C7-5; Sequence=VSP_030654, VSP_030656;
CC Name=6;
CC IsoId=Q9C0C7-6; Sequence=VSP_030654, VSP_030655, VSP_045989,
CC VSP_045990;
CC -!- INDUCTION: Negatively regulated by microRNA 7-3HG (miR7-3HG), which
CC targets the 3' untranslated (3'-UTR) region of AMBRA1 transcripts,
CC leading to a decrease of AMBRA1 mRNA and protein levels, thereby
CC inhibiting autophagy (PubMed:28059583). Strongly up-regulated during
CC egulatory T-cells (Treg) differentiation (PubMed:30513302).
CC {ECO:0000269|PubMed:28059583, ECO:0000269|PubMed:30513302}.
CC -!- DOMAIN: The PxP motifs mediate interaction with the catalytic subunit
CC of protein phosphatase 2A (PPP2CA). {ECO:0000269|PubMed:25438055,
CC ECO:0000269|PubMed:30513302}.
CC -!- DOMAIN: The TQT motifs mediate interaction with the dynein light chain
CC proteins DYNLL1 and DYNLL2, tethering AMBRA1 to the cytoskeleton in
CC absence of autophagy. {ECO:0000269|PubMed:20921139}.
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with the ATG8 family proteins GABARAP and MAP1LC3B.
CC {ECO:0000269|PubMed:25215947, ECO:0000269|PubMed:30217973}.
CC -!- PTM: Phosphorylation at Ser-52 by MTOR inhibits its ability to regulate
CC autophagy and mediate ubiquitination of ULK1 (PubMed:23524951).
CC Phosphorylation by ULK1 in response to autophagy induction abolishes
CC interaction with DYNLL1 and DYNLL2, releasing AMBRA1 from the
CC cytoskeletal docking site to induce autophagosome nucleation
CC (PubMed:20921139). Phosphorylation by MTOR inhibits interaction with
CC PPP2CA and subsequent dephosphorylation of MYC (PubMed:25438055).
CC Phosphorylation at Ser-1043 by CHUK/IKKA promotes its interaction with
CC ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity
CC (PubMed:30217973). {ECO:0000269|PubMed:20921139,
CC ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:25438055,
CC ECO:0000269|PubMed:30217973}.
CC -!- PTM: Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells,
CC leading to its degradation by the proteasome (PubMed:25499913).
CC Induction of autophagy promotes stabilization via interaction with CUL4
CC (CUL4A or CUL4B) and DDB1 (PubMed:25499913). Upon prolonged starvation,
CC ubiquitinated and degraded, terminating the autophagy response
CC (PubMed:25499913). {ECO:0000269|PubMed:25499913}.
CC -!- PTM: Undergoes proteolytic processing by caspase-6 (CASP6), caspase-7
CC (CASP7) and caspase-8 (CASP8) during apoptosis, resulting in the
CC dismantling of the autophagic machinery and the accomplishment of the
CC programmed cell death program (PubMed:22441670). Also cleaved by
CC calpains during apoptosis, which mediate a complete proteolytic
CC degradation (PubMed:22441670). {ECO:0000269|PubMed:22441670}.
CC -!- SIMILARITY: Belongs to the WD repeat AMBRA1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA91067.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAB14457.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAB21827.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- SEQUENCE CAUTION: [Isoform 6]:
CC Sequence=AL834190; Type=Frameshift; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; DQ870924; ABI74670.1; -; mRNA.
DR EMBL; AB051523; BAB21827.1; ALT_INIT; mRNA.
DR EMBL; AK000301; BAA91067.1; ALT_FRAME; mRNA.
DR EMBL; AK023197; BAB14457.1; ALT_INIT; mRNA.
DR EMBL; AL834190; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC024293; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC115097; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC116021; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC127035; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW67996.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW67999.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68001.1; -; Genomic_DNA.
DR EMBL; BC045609; AAH45609.1; -; mRNA.
DR CCDS; CCDS31475.1; -. [Q9C0C7-4]
DR CCDS; CCDS73281.1; -. [Q9C0C7-2]
DR RefSeq; NP_001254711.1; NM_001267782.1. [Q9C0C7-5]
DR RefSeq; NP_001254712.1; NM_001267783.1.
DR RefSeq; NP_001287660.1; NM_001300731.1. [Q9C0C7-2]
DR RefSeq; NP_060219.2; NM_017749.3. [Q9C0C7-4]
DR RefSeq; XP_005253066.1; XM_005253009.3. [Q9C0C7-1]
DR RefSeq; XP_005253068.1; XM_005253011.3. [Q9C0C7-3]
DR RefSeq; XP_005253071.1; XM_005253014.3.
DR RefSeq; XP_006718322.1; XM_006718259.2. [Q9C0C7-1]
DR AlphaFoldDB; Q9C0C7; -.
DR SMR; Q9C0C7; -.
DR BioGRID; 120765; 273.
DR DIP; DIP-53597N; -.
DR IntAct; Q9C0C7; 54.
DR MINT; Q9C0C7; -.
DR STRING; 9606.ENSP00000431926; -.
DR GlyGen; Q9C0C7; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; Q9C0C7; -.
DR PhosphoSitePlus; Q9C0C7; -.
DR BioMuta; AMBRA1; -.
DR DMDM; 166215833; -.
DR EPD; Q9C0C7; -.
DR jPOST; Q9C0C7; -.
DR MassIVE; Q9C0C7; -.
DR MaxQB; Q9C0C7; -.
DR PaxDb; Q9C0C7; -.
DR PeptideAtlas; Q9C0C7; -.
DR PRIDE; Q9C0C7; -.
DR ProteomicsDB; 32296; -.
DR ProteomicsDB; 79999; -. [Q9C0C7-1]
DR ProteomicsDB; 80000; -. [Q9C0C7-2]
DR ProteomicsDB; 80001; -. [Q9C0C7-3]
DR ProteomicsDB; 80002; -. [Q9C0C7-4]
DR ProteomicsDB; 80003; -. [Q9C0C7-5]
DR Antibodypedia; 26331; 437 antibodies from 36 providers.
DR DNASU; 55626; -.
DR Ensembl; ENST00000314845.7; ENSP00000318313.3; ENSG00000110497.15. [Q9C0C7-4]
DR Ensembl; ENST00000458649.6; ENSP00000415327.2; ENSG00000110497.15. [Q9C0C7-1]
DR Ensembl; ENST00000528950.1; ENSP00000433945.1; ENSG00000110497.15. [Q9C0C7-3]
DR Ensembl; ENST00000534300.5; ENSP00000431926.1; ENSG00000110497.15. [Q9C0C7-2]
DR Ensembl; ENST00000683756.1; ENSP00000508322.1; ENSG00000110497.15. [Q9C0C7-1]
DR GeneID; 55626; -.
DR KEGG; hsa:55626; -.
DR MANE-Select; ENST00000683756.1; ENSP00000508322.1; NM_001387011.1; NP_001373940.1.
DR UCSC; uc001ncu.3; human. [Q9C0C7-1]
DR CTD; 55626; -.
DR DisGeNET; 55626; -.
DR GeneCards; AMBRA1; -.
DR HGNC; HGNC:25990; AMBRA1.
DR HPA; ENSG00000110497; Low tissue specificity.
DR MIM; 611359; gene.
DR neXtProt; NX_Q9C0C7; -.
DR OpenTargets; ENSG00000110497; -.
DR PharmGKB; PA162376307; -.
DR VEuPathDB; HostDB:ENSG00000110497; -.
DR eggNOG; KOG0266; Eukaryota.
DR GeneTree; ENSGT00390000016223; -.
DR HOGENOM; CLU_008882_0_0_1; -.
DR InParanoid; Q9C0C7; -.
DR OMA; GSENWFT; -.
DR OrthoDB; 488527at2759; -.
DR PhylomeDB; Q9C0C7; -.
DR TreeFam; TF328981; -.
DR PathwayCommons; Q9C0C7; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR SignaLink; Q9C0C7; -.
DR SIGNOR; Q9C0C7; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 55626; 113 hits in 1136 CRISPR screens.
DR ChiTaRS; AMBRA1; human.
DR GenomeRNAi; 55626; -.
DR Pharos; Q9C0C7; Tbio.
DR PRO; PR:Q9C0C7; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q9C0C7; protein.
DR Bgee; ENSG00000110497; Expressed in oocyte and 201 other tissues.
DR ExpressionAtlas; Q9C0C7; baseline and differential.
DR Genevisible; Q9C0C7; HS.
DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005930; C:axoneme; ISS:UniProtKB.
DR GO; GO:0080008; C:Cul4-RING E3 ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005741; C:mitochondrial outer membrane; NAS:ParkinsonsUK-UCL.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; TAS:ParkinsonsUK-UCL.
DR GO; GO:0045335; C:phagocytic vesicle; IEA:Ensembl.
DR GO; GO:0051020; F:GTPase binding; IPI:UniProtKB.
DR GO; GO:0019903; F:protein phosphatase binding; IDA:UniProtKB.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0000045; P:autophagosome assembly; IDA:UniProtKB.
DR GO; GO:0006914; P:autophagy; IBA:GO_Central.
DR GO; GO:0000422; P:autophagy of mitochondrion; IGI:ParkinsonsUK-UCL.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0009267; P:cellular response to starvation; IEA:Ensembl.
DR GO; GO:0000423; P:mitophagy; IDA:ParkinsonsUK-UCL.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0021915; P:neural tube development; IEA:Ensembl.
DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProtKB.
DR GO; GO:1904544; P:positive regulation of free ubiquitin chain polymerization; IDA:UniProtKB.
DR GO; GO:1901526; P:positive regulation of mitophagy; IDA:UniProtKB.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; IDA:UniProtKB.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0098780; P:response to mitochondrial depolarisation; IDA:ParkinsonsUK-UCL.
DR DisProt; DP01328; -.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR SMART; SM00320; WD40; 3.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 1.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Autophagy; Cell cycle; Cell junction; Cytoplasm;
KW Cytoplasmic vesicle; Cytoskeleton; Developmental protein; Differentiation;
KW Endoplasmic reticulum; Isopeptide bond; Methylation; Mitochondrion;
KW Neurogenesis; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW Transcription; Transcription regulation; Tumor suppressor; Ubl conjugation;
KW Ubl conjugation pathway; WD repeat.
FT CHAIN 1..1298
FT /note="Activating molecule in BECN1-regulated autophagy
FT protein 1"
FT /id="PRO_0000315703"
FT REPEAT 51..90
FT /note="WD 1"
FT REPEAT 93..133
FT /note="WD 2"
FT REPEAT 135..175
FT /note="WD 3"
FT REGION 1..22
FT /note="Interaction with DDB1"
FT /evidence="ECO:0000269|PubMed:30166453"
FT REGION 254..284
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 343..413
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 458..494
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 538..561
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 590..690
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 747..796
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1060..1079
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1112..1143
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1190..1214
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1227..1298
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 275..281
FT /note="PxP motif 1"
FT /evidence="ECO:0000269|PubMed:25438055,
FT ECO:0000269|PubMed:30513302"
FT MOTIF 1043..1052
FT /note="LIR"
FT /evidence="ECO:0000269|PubMed:25215947"
FT MOTIF 1104..1106
FT /note="TQT motif 1"
FT /evidence="ECO:0000269|PubMed:20921139"
FT MOTIF 1116..1118
FT /note="TQT motif 2"
FT /evidence="ECO:0000269|PubMed:20921139"
FT MOTIF 1206..1212
FT /note="PxP motif 2"
FT /evidence="ECO:0000269|PubMed:25438055,
FT ECO:0000269|PubMed:30513302"
FT COMPBIAS 266..280
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 343..389
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 480..494
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 590..648
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 656..677
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 747..769
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1242..1260
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 482..483
FT /note="Cleavage; by caspase-6, caspase-7 and caspase-8"
FT /evidence="ECO:0000269|PubMed:22441670"
FT MOD_RES 52
FT /note="Phosphoserine; by MTOR"
FT /evidence="ECO:0000269|PubMed:23524951"
FT MOD_RES 328
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 443
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 635
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 639
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 747
FT /note="Asymmetric dimethylarginine"
FT /evidence="ECO:0000250|UniProtKB:A2AH22"
FT MOD_RES 1043
FT /note="Phosphoserine; by IKKA"
FT /evidence="ECO:0000269|PubMed:30217973"
FT MOD_RES 1205
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 45
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:A2AH22"
FT VAR_SEQ 255..344
FT /note="Missing (in isoform 4, isoform 5 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:17974005"
FT /id="VSP_030654"
FT VAR_SEQ 691..719
FT /note="Missing (in isoform 3 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:17589504,
FT ECO:0000303|PubMed:17974005"
FT /id="VSP_030655"
FT VAR_SEQ 691
FT /note="R -> RRSLALSPRLEYSGAILAHCKLRLPGSCHSPASASQVAGTTGAHHHA
FT RLIFAFLVEMEFHHVSQAGLELLTSGDLPTSASQSAGITGVSHRAWP (in isoform
FT 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_030656"
FT VAR_SEQ 721..780
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11214970"
FT /id="VSP_030657"
FT VAR_SEQ 864..880
FT /note="WWDFTKFDLPEISNASV -> GGGTSLSLTSLKSVMLP (in isoform
FT 6)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_045989"
FT VAR_SEQ 881..1298
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_045990"
FT VARIANT 80
FT /note="T -> M (found in a child with spina bifida; unknown
FT pathological significance; reduced induction of autophagy)"
FT /evidence="ECO:0000269|PubMed:32333458"
FT /id="VAR_085051"
FT VARIANT 364
FT /note="L -> F (found in a fetus with encephalocele; unknown
FT pathological significance; reduced induction of autophagy)"
FT /evidence="ECO:0000269|PubMed:32333458"
FT /id="VAR_085052"
FT VARIANT 833
FT /note="S -> F (found in a child with spina bifida; unknown
FT pathological significance; reduced induction of autophagy)"
FT /evidence="ECO:0000269|PubMed:32333458"
FT /id="VAR_085053"
FT VARIANT 974
FT /note="M -> V (found in a fetus with encephalocele and
FT spina bifida; unknown pathological significance; reduced
FT induction of autophagy)"
FT /evidence="ECO:0000269|PubMed:32333458"
FT /id="VAR_085054"
FT VARIANT 1043
FT /note="S -> F (found in a fetus with anencephaly and spina
FT bifida; unknown pathological significance; does not impair
FT induction of autophagy)"
FT /evidence="ECO:0000269|PubMed:32333458"
FT /id="VAR_085055"
FT MUTAGEN 1..43
FT /note="Missing: Abolished interaction with DDB1."
FT /evidence="ECO:0000269|PubMed:30166453"
FT MUTAGEN 1..22
FT /note="Missing: Abolished interaction with DDB1."
FT /evidence="ECO:0000269|PubMed:30166453"
FT MUTAGEN 52
FT /note="S->A: Impaired phosphorylation by MTOR, leading to
FT strong induction of autophagy. Does not affect interaction
FT with DDB1."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 52
FT /note="S->E: Phospho-mimetic mutant; abolished ability to
FT promote autophagy. Does not affect interaction with DDB1."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 275..277
FT /note="PQP->AQA: Abolished interaction with PPP2CA and MYC,
FT leading to decreased MYC dephosphorylation; when associated
FT with 1206-A--A-1208. Abolished interaction with PPP2CA and
FT FOXO3, leading to decreased FOXO3 dephosphorylation; when
FT associated with 1206-A--A-1208."
FT /evidence="ECO:0000269|PubMed:25438055,
FT ECO:0000269|PubMed:30513302"
FT MUTAGEN 482
FT /note="D->A: Abolished cleavage by caspases without
FT affecting cleavage by calpains."
FT /evidence="ECO:0000269|PubMed:22441670"
FT MUTAGEN 620
FT /note="E->A: Abolished interaction with TRAF6."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 642
FT /note="E->A: Does not affect interaction with TRAF6."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 682
FT /note="E->A: Abolished interaction with TRAF6."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 918
FT /note="E->A: Does not affect interaction with TRAF6."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 1043
FT /note="S->A: Abolished phosphorylation by CHUK/IKKA,
FT leading to impaired interaction with ATG8 family proteins
FT and reduced mitophagic activity."
FT /evidence="ECO:0000269|PubMed:30217973"
FT MUTAGEN 1043
FT /note="S->D: Phospho-mimetic mutant; increased interaction
FT with ATG8 family proteins and increased mitophagic
FT activity."
FT /evidence="ECO:0000269|PubMed:30217973"
FT MUTAGEN 1049..1052
FT /note="WDQL->ADQA: Abolished interaction with LC3
FT (MAP1LC3A, MAP1LC3B or MAP1LC3C)."
FT /evidence="ECO:0000269|PubMed:25215947"
FT MUTAGEN 1105
FT /note="Q->A: In TAT1 mutant; abolished interaction with
FT DYNLL1 and DYNLL2, leading to constitutive induction of
FT autophagy."
FT /evidence="ECO:0000269|PubMed:20921139"
FT MUTAGEN 1117
FT /note="Q->A: In TAT2 mutant; abolished interaction with
FT DYNLL1 and DYNLL2, leading to constitutive induction of
FT autophagy."
FT /evidence="ECO:0000269|PubMed:20921139"
FT MUTAGEN 1134
FT /note="E->A: Does not affect interaction with TRAF6."
FT /evidence="ECO:0000269|PubMed:23524951"
FT MUTAGEN 1206..1208
FT /note="PQP->AQA: Abolished interaction with PPP2CA and MYC,
FT leading to decreased MYC dephosphorylation; when associated
FT with 275-A--A-277. Abolished interaction with PPP2CA and
FT FOXO3, leading to decreased FOXO3 dephosphorylation; when
FT associated with 275-A--A-277."
FT /evidence="ECO:0000269|PubMed:25438055"
FT CONFLICT 165
FT /note="W -> R (in Ref. 3; BAA91067)"
FT /evidence="ECO:0000305"
FT CONFLICT 793
FT /note="N -> K (in Ref. 4; AL834190)"
FT /evidence="ECO:0000305"
FT CONFLICT 869
FT /note="K -> E (in Ref. 3; BAB14457)"
FT /evidence="ECO:0000305"
FT CONFLICT 983
FT /note="Q -> L (in Ref. 3; BAB14457)"
FT /evidence="ECO:0000305"
FT CONFLICT 1105
FT /note="Q -> E (in Ref. 7; AAH45609)"
FT /evidence="ECO:0000305"
FT CONFLICT 1268
FT /note="L -> V (in Ref. 7; AAH45609)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1298 AA; 142507 MW; 44FE9CDFFFE6811E CRC64;
MKVVPEKNAV RILWGRERGA RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA
FSPDRTLLAS THVNHNIYIT EVKTGKCVHS LIGHRRTPWC VTFHPTISGL IASGCLDGEV
RIWDLHGGSE SWFTDSNNAI ASLAFHPTAQ LLLIATANEI HFWDWSRREP FAVVKTASEM
ERVRLVRFDP LGHYLLTAIV NPSNQQGDDE PEIPIDGTEL SHYRQRALLQ SQPVRRTPLL
HNFLHMLSSR SSGIQVGEQS TVQDSATPSP PPPPPQPSTE RPRTSAYIRL RQRVSYPTAE
CCQHLGILCL CSRCSGTRVP SLLPHQDSVP PASARATTPS FSFVQTEPFH PPEQASSTQQ
DQGLLNRPSA FSTVQSSTAG NTLRNLSLGP TRRSLGGPLS SHPSRYHREI APGLTGSEWT
RTVLSLNSRS EAESMPPPRT SASSVSLLSV LRQQEGGSQA SVYTSATEGR GFPASGLATE
SDGGNGSSQN NSGSIRHELQ CDLRRFFLEY DRLQELDQSL SGEAPQTQQA QEMLNNNIES
ERPGPSHQPT PHSSENNSNL SRGHLNRCRA CHNLLTFNND TLRWERTTPN YSSGEASSSW
QVPSSFESVP SSGSQLPPLE RTEGQTPSSS RLELSSSASP QEERTVGVAF NQETGHWERI
YTQSSRSGTV SQEALHQDMP EESSEEDSLR RRLLESSLIS LSRYDGAGSR EHPIYPDPAR
LSPAAYYAQR MIQYLSRRDS IRQRSMRYQQ NRLRSSTSSS SSDNQGPSVE GTDLEFEDFE
DNGDRSRHRA PRNARMSAPS LGRFVPRRFL LPEYLPYAGI FHERGQPGLA THSSVNRVLA
GAVIGDGQSA VASNIANTTY RLQWWDFTKF DLPEISNASV NVLVQNCKIY NDASCDISAD
GQLLAAFIPS SQRGFPDEGI LAVYSLAPHN LGEMLYTKRF GPNAISVSLS PMGRYVMVGL
ASRRILLHPS TEHMVAQVFR LQQAHGGETS MRRVFNVLYP MPADQRRHVS INSARWLPEP
GLGLAYGTNK GDLVICRPEA LNSGVEYYWD QLNETVFTVH SNSRSSERPG TSRATWRTDR
DMGLMNAIGL QPRNPATSVT SQGTQTLALQ LQNAETQTER EVPEPGTAAS GPGEGEGSEY
GASGEDALSR IQRLMAEGGM TAVVQREQST TMASMGGFGN NIIVSHRIHR SSQTGTEPGA
AHTSSPQPST SRGLLPEAGQ LAERGLSPRT ASWDQPGTPG REPTQPTLPS SSPVPIPVSL
PSAEGPTLHC ELTNNNHLLD GGSSRGDAAG PRGEPRNR
