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 28-JAN-2026, entry version 178. 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, GN ECO:0000312|HGNC:HGNC:25990}; GN Synonyms=DCAF3 {ECO:0000303|PubMed:16949367}, KIAA1736 GN {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 ERRATUM OF PUBMED:25438055. RX PubMed=25925585; DOI=10.1038/ncb3171; 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.; RL Nat. Cell Biol. 17:706-706(2015). RN [28] 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 [29] 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 [30] 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 [31] 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 [32] 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 [33] 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 [34] 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 [35] 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 [36] 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 [37] 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:32333458, PubMed:33854232, PubMed:33854235, PubMed:33854239). 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:25438055, CC PubMed:25803737). 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:16949367, PubMed:25499913, 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; P63167: DYNLL1; NbExp=4; IntAct=EBI-2512975, EBI-349105; CC Q9C0C7; Q96FJ2: DYNLL2; NbExp=4; IntAct=EBI-2512975, EBI-742371; 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). Also localizes 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 CCDS; CCDS91466.1; -. [Q9C0C7-1] DR RefSeq; NP_001254711.1; NM_001267782.2. [Q9C0C7-5] DR RefSeq; NP_001254712.1; NM_001267783.1. DR RefSeq; NP_001287660.1; NM_001300731.2. [Q9C0C7-2] DR RefSeq; NP_001354397.1; NM_001367468.1. [Q9C0C7-1] DR RefSeq; NP_001354400.1; NM_001367471.1. [Q9C0C7-4] DR RefSeq; NP_001373940.1; NM_001387011.1. [Q9C0C7-1] DR RefSeq; NP_060219.2; NM_017749.3. [Q9C0C7-4] DR PDB; 8WQR; EM; 3.08 A; B=1-204. DR PDB; 9IVD; EM; 3.55 A; B=1-1044. DR PDBsum; 8WQR; -. DR PDBsum; 9IVD; -. DR AlphaFoldDB; Q9C0C7; -. DR EMDB; EMD-37752; -. DR EMDB; EMD-60925; -. DR SMR; Q9C0C7; -. DR BioGRID; 120765; 316. DR ComplexPortal; CPX-2778; CRL4-AMBRA1 E3 ubiquitin ligase complex, CUL4B variant. DR ComplexPortal; CPX-2797; CRL4-AMBRA1 E3 ubiquitin ligase complex, CUL4A variant. DR DIP; DIP-53597N; -. DR FunCoup; Q9C0C7; 3523. DR IntAct; Q9C0C7; 92. DR MINT; Q9C0C7; -. DR STRING; 9606.ENSP00000431926; -. DR GlyCosmos; Q9C0C7; 3 sites, 1 glycan. DR GlyGen; Q9C0C7; 11 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (9 sites). DR iPTMnet; Q9C0C7; -. DR PhosphoSitePlus; Q9C0C7; -. DR BioMuta; AMBRA1; -. DR DMDM; 166215833; -. DR jPOST; Q9C0C7; -. DR MassIVE; Q9C0C7; -. DR PaxDb; 9606-ENSP00000431926; -. DR PeptideAtlas; 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 Pumba; Q9C0C7; -. DR Antibodypedia; 26331; 410 antibodies from 35 providers. DR DNASU; 55626; -. DR Ensembl; ENST00000314845.7; ENSP00000318313.3; ENSG00000110497.16. [Q9C0C7-4] DR Ensembl; ENST00000458649.6; ENSP00000415327.2; ENSG00000110497.16. [Q9C0C7-1] DR Ensembl; ENST00000528950.1; ENSP00000433945.1; ENSG00000110497.16. [Q9C0C7-3] DR Ensembl; ENST00000534300.5; ENSP00000431926.1; ENSG00000110497.16. [Q9C0C7-2] DR Ensembl; ENST00000683756.1; ENSP00000508322.1; ENSG00000110497.16. [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 AGR; HGNC:25990; -. DR ClinPGx; PA162376307; -. 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 OpenTargets; ENSG00000110497; -. DR VEuPathDB; HostDB:ENSG00000110497; -. DR eggNOG; KOG0266; Eukaryota. DR GeneTree; ENSGT00390000016223; -. DR HOGENOM; CLU_008882_0_0_1; -. DR InParanoid; Q9C0C7; -. DR OMA; TTECCQH; -. DR OrthoDB; 6363363at2759; -. DR PAN-GO; Q9C0C7; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q9C0C7; -. DR PathwayCommons; Q9C0C7; -. DR Reactome; R-HSA-1632852; Macroautophagy. DR SignaLink; Q9C0C7; -. DR SIGNOR; Q9C0C7; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000110497; -. DR BioGRID-ORCS; 55626; 119 hits in 1217 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 202 other cell types or tissues. DR ExpressionAtlas; Q9C0C7; baseline and differential. 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: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:0072542; F:protein phosphatase activator activity; IDA:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990756; F:ubiquitin-like ligase-substrate adaptor activity; IDA:UniProt. DR GO; GO:0000045; P:autophagosome assembly; IDA:UniProt. 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:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProt. 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 FunFam; 2.130.10.10:FF:000057; Activating molecule in BECN1-regulated autophagy protein 1 isoform X1; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR052596; AMBRA1_autophagy. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR InterPro; IPR019775; WD40_repeat_CS. DR InterPro; IPR036322; WD40_repeat_dom_sf. DR InterPro; IPR001680; WD40_rpt. DR PANTHER; PTHR22874; ACTIVATING MOLECULE IN BECN1-REGULATED AUTOPHAGY PROTEIN 1; 1. DR PANTHER; PTHR22874:SF1; ACTIVATING MOLECULE IN BECN1-REGULATED AUTOPHAGY PROTEIN 1; 1. DR Pfam; PF00400; WD40; 1. DR SMART; SM00320; WD40; 3. DR SUPFAM; SSF50978; WD40 repeat-like; 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 3D-structure; Alternative splicing; Autophagy; Cell cycle; Cell junction; KW Cytoplasm; Cytoplasmic vesicle; Cytoskeleton; Developmental protein; KW Differentiation; Endoplasmic reticulum; Isopeptide bond; Methylation; KW Mitochondrion; Neurogenesis; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Transcription; KW 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 254..266 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 268..277 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 354..385 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 458..467 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 547..561 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 590..601 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 602..614 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 628..639 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 661..674 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 772..781 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1060..1075 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1191..1212 FT /note="Polar 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; FT uncertain 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; FT uncertain 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; FT uncertain 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; uncertain significance; reduced induction of FT 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; uncertain significance; does not impair induction FT 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" FT HELIX 9..17 FT /evidence="ECO:0007829|PDB:8WQR" FT HELIX 25..37 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 56..61 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 63..66 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 68..72 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 75..80 FT /evidence="ECO:0007829|PDB:8WQR" FT TURN 82..84 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 87..92 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 98..102 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 105..107 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 110..115 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 118..127 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 129..133 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 142..146 FT /evidence="ECO:0007829|PDB:8WQR" FT TURN 147..150 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 151..163 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 167..169 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 172..175 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 183..188 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 192..200 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 860..866 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 878..887 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 899..902 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 904..908 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 920..924 FT /evidence="ECO:0007829|PDB:8WQR" FT HELIX 928..930 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 934..939 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 944..949 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 953..960 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 976..981 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 985..987 FT /evidence="ECO:0007829|PDB:8WQR" FT HELIX 988..990 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 991..997 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 1011..1016 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 1024..1028 FT /evidence="ECO:0007829|PDB:8WQR" FT STRAND 1033..1036 FT /evidence="ECO:0007829|PDB:8WQR" 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 //