ATG4B_HUMAN
ID ATG4B_HUMAN Reviewed; 393 AA.
AC Q9Y4P1; B7WNK2; Q53NU4; Q6ZUV8; Q8WYM9; Q96K07; Q96K96; Q96SZ1; Q9Y2F2;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Cysteine protease ATG4B {ECO:0000305};
DE EC=3.4.22.- {ECO:0000269|PubMed:21177865, ECO:0000269|PubMed:22302004};
DE AltName: Full=AUT-like 1 cysteine endopeptidase;
DE AltName: Full=Autophagy-related cysteine endopeptidase 1 {ECO:0000303|PubMed:12446702};
DE Short=Autophagin-1 {ECO:0000303|PubMed:12446702};
DE AltName: Full=Autophagy-related protein 4 homolog B {ECO:0000303|PubMed:15187094};
DE Short=HsAPG4B {ECO:0000303|PubMed:29458288};
DE Short=hAPG4B {ECO:0000303|PubMed:15187094};
GN Name=ATG4B {ECO:0000303|PubMed:15187094, ECO:0000312|HGNC:HGNC:20790};
GN Synonyms=APG4B {ECO:0000303|PubMed:15187094},
GN AUTL1 {ECO:0000312|HGNC:HGNC:20790},
GN KIAA0943 {ECO:0000303|PubMed:10231032};
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 RETRACTED PAPER.
RC TISSUE=Liver;
RX PubMed=12446702; DOI=10.1074/jbc.m208247200;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RT "Human autophagins, a family of cysteine proteinases potentially implicated
RT in cell degradation by autophagy.";
RL J. Biol. Chem. 278:3671-3678(2003).
RN [2]
RP RETRACTION NOTICE OF PUBMED:12446702.
RX PubMed=30808002; DOI=10.1074/jbc.w118.007325;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RL J. Biol. Chem. 294:1431-1431(2019).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN GABARAPL2; GABARAP AND
RP MAP1LC3A CLEAVAGE, ACTIVE SITE, MUTAGENESIS OF CYS-74, AND VARIANT GLN-354.
RX PubMed=15169837; DOI=10.1242/jcs.01131;
RA Kabeya Y., Mizushima N., Yamamoto A., Oshitani-Okamoto S., Ohsumi Y.,
RA Yoshimori T.;
RT "LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on
RT form-II formation.";
RL J. Cell Sci. 117:2805-2812(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-354.
RC TISSUE=Brain;
RX PubMed=10231032; DOI=10.1093/dnares/6.1.63;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:63-70(1999).
RN [5]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R.;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4 AND 6).
RC TISSUE=Embryo, and Placenta;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-354.
RC TISSUE=Testis;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-354.
RC TISSUE=Placenta;
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 [10]
RP PROTEIN SEQUENCE OF 1-12; 33-49; 120-137; 185-201 AND 230-244, ACETYLATION
RP AT MET-1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V.;
RL Submitted (JAN-2010) to UniProtKB.
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF CYS-74.
RX PubMed=15187094; DOI=10.1074/jbc.m401461200;
RA Tanida I., Sou Y.-S., Ezaki J., Minematsu-Ikeguchi N., Ueno T.,
RA Kominami E.;
RT "HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human
RT Atg8 homologues and delipidates microtubule-associated protein light chain
RT 3- and GABAA receptor-associated protein-phospholipid conjugates.";
RL J. Biol. Chem. 279:36268-36276(2004).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [13]
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-78.
RX PubMed=17347651; DOI=10.1038/sj.emboj.7601623;
RA Scherz-Shouval R., Shvets E., Fass E., Shorer H., Gil L., Elazar Z.;
RT "Reactive oxygen species are essential for autophagy and specifically
RT regulate the activity of Atg4.";
RL EMBO J. 26:1749-1760(2007).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, 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 [17]
RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF CYS-74.
RX PubMed=20818167; DOI=10.4161/auto.6.7.13075;
RA Shu C.W., Drag M., Bekes M., Zhai D., Salvesen G.S., Reed J.C.;
RT "Synthetic substrates for measuring activity of autophagy proteases:
RT autophagins (Atg4).";
RL Autophagy 6:936-947(2010).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, 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 [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION.
RX PubMed=21177865; DOI=10.1074/jbc.m110.199059;
RA Li M., Hou Y., Wang J., Chen X., Shao Z.M., Yin X.M.;
RT "Kinetics comparisons of mammalian Atg4 homologues indicate selective
RT preferences toward diverse Atg8 substrates.";
RL J. Biol. Chem. 286:7327-7338(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=22302004; DOI=10.4161/auto.18777;
RA Li M., Chen X., Ye Q.Z., Vogt A., Yin X.M.;
RT "A high-throughput FRET-based assay for determination of Atg4 activity.";
RL Autophagy 8:401-412(2012).
RN [23]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [24]
RP UBIQUITINATION.
RX PubMed=23093945; DOI=10.1371/journal.pgen.1003007;
RA Kuang E., Okumura C.Y., Sheffy-Levin S., Varsano T., Shu V.C., Qi J.,
RA Niesman I.R., Yang H.J., Lopez-Otin C., Yang W.Y., Reed J.C., Broday L.,
RA Nizet V., Ronai Z.A.;
RT "Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and
RT influences susceptibility to bacterial infection.";
RL PLoS Genet. 8:e1003007-e1003007(2012).
RN [25]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP 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 [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [27]
RP FUNCTION, ACTIVE SITE, PHOSPHORYLATION AT SER-383 AND SER-392, AND
RP MUTAGENESIS OF CYS-74; SER-383 AND SER-392.
RX PubMed=26378241; DOI=10.1074/jbc.m115.658088;
RA Yang Z., Wilkie-Grantham R.P., Yanagi T., Shu C.W., Matsuzawa S.,
RA Reed J.C.;
RT "ATG4B (Autophagin-1) phosphorylation modulates autophagy.";
RL J. Biol. Chem. 290:26549-26561(2015).
RN [28]
RP FUNCTION, AND GLYCOSYLATION.
RX PubMed=27527864; DOI=10.18632/oncotarget.11083;
RA Jo Y.K., Park N.Y., Park S.J., Kim B.G., Shin J.H., Jo D.S., Bae D.J.,
RA Suh Y.A., Chang J.H., Lee E.K., Kim S.Y., Kim J.C., Cho D.H.;
RT "O-GlcNAcylation of ATG4B positively regulates autophagy by increasing its
RT hydroxylase activity.";
RL Oncotarget 7:57186-57196(2016).
RN [29]
RP FUNCTION, S-NITROSYLATION AT CYS-189; CYS-292 AND CYS-301, AND MUTAGENESIS
RP OF CYS-189; CYS-292 AND CYS-301.
RX PubMed=28633005; DOI=10.1080/15548627.2017.1320467;
RA Li Y., Zhang Y., Wang L., Wang P., Xue Y., Li X., Qiao X., Zhang X., Xu T.,
RA Liu G., Li P., Chen C.;
RT "Autophagy impairment mediated by S-nitrosation of ATG4B leads to
RT neurotoxicity in response to hyperglycemia.";
RL Autophagy 13:1145-1160(2017).
RN [30]
RP FUNCTION, PHOSPHORYLATION AT SER-383, AND MUTAGENESIS OF SER-383.
RX PubMed=29232556; DOI=10.1016/j.ccell.2017.11.005;
RA Huang T., Kim C.K., Alvarez A.A., Pangeni R.P., Wan X., Song X., Shi T.,
RA Yang Y., Sastry N., Horbinski C.M., Lu S., Stupp R., Kessler J.A.,
RA Nishikawa R., Nakano I., Sulman E.P., Lu X., James C.D., Yin X.M., Hu B.,
RA Cheng S.Y.;
RT "MST4 phosphorylation of ATG4B regulates autophagic activity,
RT tumorigenicity, and radioresistance in glioblastoma.";
RL Cancer Cell 32:840-855(2017).
RN [31]
RP FUNCTION, ACTIVE SITE, PHOSPHORYLATION AT SER-316, AND MUTAGENESIS OF
RP CYS-74 AND SER-316.
RX PubMed=28821708; DOI=10.1038/s41467-017-00303-2;
RA Pengo N., Agrotis A., Prak K., Jones J., Ketteler R.;
RT "A reversible phospho-switch mediated by ULK1 regulates the activity of
RT autophagy protease ATG4B.";
RL Nat. Commun. 8:294-294(2017).
RN [32]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-34.
RX PubMed=29165041; DOI=10.1080/15548627.2017.1407887;
RA Ni Z., He J., Wu Y., Hu C., Dai X., Yan X., Li B., Li X., Xiong H., Li Y.,
RA Li S., Xu L., Li Y., Lian J., He F.;
RT "AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and
RT enhances the Warburg effect in hepatocellular carcinoma cells.";
RL Autophagy 14:685-701(2018).
RN [33]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF 388-PHE--LEU-391.
RX PubMed=29458288; DOI=10.1080/15548627.2018.1437341;
RA Kauffman K.J., Yu S., Jin J., Mugo B., Nguyen N., O'Brien A., Nag S.,
RA Lystad A.H., Melia T.J.;
RT "Delipidation of mammalian Atg8-family proteins by each of the four ATG4
RT proteases.";
RL Autophagy 14:992-1010(2018).
RN [34]
RP FUNCTION, PHOSPHORYLATION AT SER-34, ACTIVE SITE, AND MUTAGENESIS OF
RP SER-34; CYS-74; SER-121 AND SER-262.
RX PubMed=30443548; DOI=10.3389/fcell.2018.00148;
RA Pengo N., Prak K., Costa J.R., Luft C., Agrotis A., Freeman J.,
RA Gewinner C.A., Chan A.W.E., Selwood D.L., Kriston-Vizi J., Ketteler R.;
RT "Identification of kinases and phosphatases that regulate ATG4B activity by
RT siRNA and small molecule screening in cells.";
RL Front. Cell Dev. Biol. 6:148-148(2018).
RN [35]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=30076329; DOI=10.1038/s41598-018-29900-x;
RA Bosc D., Vezenkov L., Bortnik S., An J., Xu J., Choutka C., Hannigan A.M.,
RA Kovacic S., Loo S., Clark P.G.K., Chen G., Guay-Ross R.N., Yang K.,
RA Dragowska W.H., Zhang F., Go N.E., Leung A., Honson N.S., Pfeifer T.A.,
RA Gleave M., Bally M., Jones S.J., Gorski S.M., Young R.N.;
RT "A new quinoline-based chemical probe inhibits the autophagy-related
RT cysteine protease ATG4B.";
RL Sci. Rep. 8:11653-11653(2018).
RN [36]
RP FUNCTION.
RX PubMed=30661429; DOI=10.1080/15548627.2019.1569925;
RA Agrotis A., Pengo N., Burden J.J., Ketteler R.;
RT "Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP
RT processing revealed in cells.";
RL Autophagy 15:976-997(2019).
RN [37]
RP FUNCTION.
RX PubMed=31315929; DOI=10.1074/jbc.ac119.009977;
RA Agrotis A., von Chamier L., Oliver H., Kiso K., Singh T., Ketteler R.;
RT "Human ATG4 autophagy proteases counteract attachment of ubiquitin-like
RT LC3/GABARAP proteins to other cellular proteins.";
RL J. Biol. Chem. 294:12610-12621(2019).
RN [38]
RP DISULFIDE BONDS, AND MUTAGENESIS OF CYS-78; CYS-89; CYS-183; CYS-189;
RP CYS-203; CYS-246; CYS-292; CYS-301; CYS-306; CYS-323; CYS-333 AND CYS-361.
RX PubMed=31880198; DOI=10.1080/15548627.2019.1709763;
RA Zheng X., Yang Z., Gu Q., Xia F., Fu Y., Liu P., Yin X.M., Li M.;
RT "The protease activity of human ATG4B is regulated by reversible oxidative
RT modification.";
RL Autophagy 16:1838-1850(2020).
RN [39]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32686895; DOI=10.1002/cbic.202000359;
RA Yang A., Pantoom S., Wu Y.W.;
RT "Distinct mechanisms for processing autophagy protein LC3-PE by RavZ and
RT ATG4B.";
RL ChemBioChem 21:3377-3382(2020).
RN [40]
RP INTERACTION WITH PFKP, AND PHOSPHORYLATION AT SER-34.
RX PubMed=33607258; DOI=10.1016/j.cellsig.2021.109956;
RA Li X., Sun L., Yan G., Yan X.;
RT "PFKP facilitates ATG4B phosphorylation during amino acid deprivation-
RT induced autophagy.";
RL Cell. Signal. 82:109956-109956(2021).
RN [41]
RP FUNCTION.
RX PubMed=33773106; DOI=10.1016/j.molcel.2021.03.001;
RA Nguyen T.N., Padman B.S., Zellner S., Khuu G., Uoselis L., Lam W.K.,
RA Skulsuppaisarn M., Lindblom R.S.J., Watts E.M., Behrends C., Lazarou M.;
RT "ATG4 family proteins drive phagophore growth independently of the
RT LC3/GABARAP lipidation system.";
RL Mol. Cell 81:2013-2030(2021).
RN [42]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=33909989; DOI=10.1016/j.molcel.2021.03.020;
RA Durgan J., Lystad A.H., Sloan K., Carlsson S.R., Wilson M.I., Marcassa E.,
RA Ulferts R., Webster J., Lopez-Clavijo A.F., Wakelam M.J., Beale R.,
RA Simonsen A., Oxley D., Florey O.;
RT "Non-canonical autophagy drives alternative ATG8 conjugation to
RT phosphatidylserine.";
RL Mol. Cell 81:2031-2040(2021).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS), ACTIVE SITE, AND MUTAGENESIS OF
RP CYS-74; TRP-142; ARG-229; ASP-278 AND HIS-280.
RX PubMed=16183633; DOI=10.1074/jbc.m509158200;
RA Sugawara K., Suzuki N.N., Fujioka Y., Mizushima N., Ohsumi Y., Inagaki F.;
RT "Structural basis for the specificity and catalysis of human Atg4B
RT responsible for mammalian autophagy.";
RL J. Biol. Chem. 280:40058-40065(2005).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), ACTIVE SITE, AND MUTAGENESIS OF
RP CYS-74; ASP-278 AND HIS-280.
RX PubMed=16325851; DOI=10.1016/j.jmb.2005.11.018;
RA Kumanomidou T., Mizushima T., Komatsu M., Suzuki A., Tanida I., Sou Y.-S.,
RA Ueno T., Kominami E., Tanaka K., Yamane T.;
RT "The crystal structure of human Atg4b, a processing and de-conjugating
RT enzyme for autophagosome-forming modifiers.";
RL J. Mol. Biol. 355:612-618(2006).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-353 IN COMPLEX WITH RAT
RP MAP1LC3B/LC3, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=19322194; DOI=10.1038/emboj.2009.80;
RA Satoo K., Noda N.N., Kumeta H., Fujioka Y., Mizushima N., Ohsumi Y.,
RA Inagaki F.;
RT "The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing
RT and delipidation during autophagy.";
RL EMBO J. 28:1341-1350(2009).
RN [46] {ECO:0007744|PDB:5LXH, ECO:0007744|PDB:5LXI}
RP X-RAY CRYSTALLOGRAPHY (1.44 ANGSTROMS) OF 384-393 IN COMPLEX WITH
RP GABARAPL1, FUNCTION, MOTIF, DOMAIN, AND MUTAGENESIS OF SER-383;
RP 388-PHE--LEU-391 AND SER-392.
RX PubMed=28287329; DOI=10.1080/15548627.2017.1287651;
RA Skytte Rasmussen M., Mouilleron S., Kumar Shrestha B., Wirth M., Lee R.,
RA Bowitz Larsen K., Abudu Princely Y., O'Reilly N., Sjottem E., Tooze S.A.,
RA Lamark T., Johansen T.;
RT "ATG4B contains a C-terminal LIR motif important for binding and efficient
RT cleavage of mammalian orthologs of yeast Atg8.";
RL Autophagy 13:834-853(2017).
CC -!- FUNCTION: Cysteine protease that plays a key role in autophagy by
CC mediating both proteolytic activation and delipidation of ATG8 family
CC proteins (PubMed:15169837, PubMed:15187094, PubMed:17347651,
CC PubMed:19322194, PubMed:21177865, PubMed:26378241, PubMed:29232556,
CC PubMed:28821708, PubMed:30443548, PubMed:30661429, PubMed:22302004,
CC PubMed:27527864, PubMed:28633005, PubMed:30076329). Required for
CC canonical autophagy (macroautophagy), non-canonical autophagy as well
CC as for mitophagy (PubMed:33773106, PubMed:33909989). The protease
CC activity is required for proteolytic activation of ATG8 family
CC proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3A,
CC MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP, to reveal a C-
CC terminal glycine (PubMed:15169837, PubMed:15187094, PubMed:17347651,
CC PubMed:20818167, PubMed:19322194, PubMed:21177865, PubMed:22302004,
CC PubMed:27527864, PubMed:28633005, PubMed:29458288, PubMed:30661429,
CC PubMed:28287329). Exposure of the glycine at the C-terminus is
CC essential for ATG8 proteins conjugation to phosphatidylethanolamine
CC (PE) and insertion to membranes, which is necessary for autophagy
CC (PubMed:15169837, PubMed:15187094, PubMed:17347651, PubMed:19322194,
CC PubMed:21177865, PubMed:22302004). Protease activity is also required
CC to counteract formation of high-molecular weight conjugates of ATG8
CC proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that
CC removes ATG8 conjugated to other proteins, such as ATG3
CC (PubMed:31315929, PubMed:33773106). In addition to the protease
CC activity, also mediates delipidation of ATG8 family proteins
CC (PubMed:15187094, PubMed:28633005, PubMed:29458288, PubMed:32686895,
CC PubMed:33909989, PubMed:19322194). Catalyzes delipidation of PE-
CC conjugated forms of ATG8 proteins during macroautophagy
CC (PubMed:15187094, PubMed:29458288, PubMed:32686895, PubMed:33909989,
CC PubMed:19322194). Also involved in non-canonical autophagy, a parallel
CC pathway involving conjugation of ATG8 proteins to single membranes at
CC endolysosomal compartments, by catalyzing delipidation of ATG8 proteins
CC conjugated to phosphatidylserine (PS) (PubMed:33909989). Compared to
CC other members of the family (ATG4A, ATG4C or ATG4C), constitutes the
CC major protein for proteolytic activation of ATG8 proteins, while it
CC displays weaker delipidation activity than other ATG4 paralogs
CC (PubMed:29458288, PubMed:30661429). Involved in phagophore growth
CC during mitophagy independently of its protease activity and of ATG8
CC proteins: acts by regulating ATG9A trafficking to mitochondria and
CC promoting phagophore-endoplasmic reticulum contacts during the lipid
CC transfer phase of mitophagy (PubMed:33773106).
CC {ECO:0000269|PubMed:15169837, ECO:0000269|PubMed:15187094,
CC ECO:0000269|PubMed:17347651, ECO:0000269|PubMed:19322194,
CC ECO:0000269|PubMed:20818167, ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004, ECO:0000269|PubMed:26378241,
CC ECO:0000269|PubMed:27527864, ECO:0000269|PubMed:28287329,
CC ECO:0000269|PubMed:28633005, ECO:0000269|PubMed:28821708,
CC ECO:0000269|PubMed:29232556, ECO:0000269|PubMed:29458288,
CC ECO:0000269|PubMed:30076329, ECO:0000269|PubMed:30443548,
CC ECO:0000269|PubMed:30661429, ECO:0000269|PubMed:31315929,
CC ECO:0000269|PubMed:32686895, ECO:0000269|PubMed:33773106,
CC ECO:0000269|PubMed:33909989}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-
CC phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-
CC glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine;
CC Xref=Rhea:RHEA:67548, Rhea:RHEA-COMP:17323, Rhea:RHEA-COMP:17324,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:64612, ChEBI:CHEBI:172940,
CC ChEBI:CHEBI:172941; Evidence={ECO:0000269|PubMed:15187094,
CC ECO:0000269|PubMed:19322194, ECO:0000269|PubMed:29458288,
CC ECO:0000269|PubMed:32686895, ECO:0000269|PubMed:33909989};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000269|PubMed:15187094, ECO:0000269|PubMed:19322194,
CC ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:32686895,
CC ECO:0000269|PubMed:33909989};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylserine +
CC H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-
CC glycero-3-phospho-L-serine; Xref=Rhea:RHEA:67576, Rhea:RHEA-
CC COMP:17324, Rhea:RHEA-COMP:17326, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57262, ChEBI:CHEBI:172940, ChEBI:CHEBI:172942;
CC Evidence={ECO:0000269|PubMed:33909989};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67577;
CC Evidence={ECO:0000269|PubMed:33909989};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide (PubMed:21177865).
CC Redox-regulated during autophagy since reducing conditions activate
CC ATG4A whereas an oxidizing environment such as the presence of H(2)O(2)
CC inhibits its activity (PubMed:17347651). The cysteine protease activity
CC compounds is inhibited by styrylquinoline compounds 4-28 and LV-320
CC (PubMed:30076329). {ECO:0000269|PubMed:17347651,
CC ECO:0000269|PubMed:21177865, ECO:0000269|PubMed:30076329}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5.1 uM for MAP1LC3B {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=5.8 uM for GABARAP {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=4.4 uM for GABARAPL1 {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=6.1 uM for GABARAPL2 {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC -!- SUBUNIT: Interacts with PFKP; promoting phosphorylation of ATG4B at
CC Ser-34 (PubMed:33607258). Interacts with GBP7 (By similarity).
CC {ECO:0000250|UniProtKB:Q8BGE6, ECO:0000269|PubMed:33607258}.
CC -!- INTERACTION:
CC Q9Y4P1; O95166: GABARAP; NbExp=8; IntAct=EBI-712014, EBI-712001;
CC Q9Y4P1; Q9H0R8: GABARAPL1; NbExp=10; IntAct=EBI-712014, EBI-746969;
CC Q9Y4P1; P60520: GABARAPL2; NbExp=10; IntAct=EBI-712014, EBI-720116;
CC Q9Y4P1; Q9H492: MAP1LC3A; NbExp=6; IntAct=EBI-712014, EBI-720768;
CC Q9Y4P1; Q9GZQ8: MAP1LC3B; NbExp=14; IntAct=EBI-712014, EBI-373144;
CC Q9Y4P1; Q9BXW4: MAP1LC3C; NbExp=4; IntAct=EBI-712014, EBI-2603996;
CC Q9Y4P1; A0A0H3LAC5: ERDMAN_2289; Xeno; NbExp=2; IntAct=EBI-712014, EBI-25401874;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:29165041}.
CC Cytoplasm, cytosol {ECO:0000269|PubMed:29165041}. Cytoplasmic vesicle,
CC autophagosome {ECO:0000269|PubMed:29165041}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:29165041}. Mitochondrion
CC {ECO:0000269|PubMed:29165041}. Note=Mainly localizes to the cytoplasm,
CC including cytosol (PubMed:29165041). A samll potion localizes to
CC mitochondria; phosphorylation at Ser-34 promotes localization to
CC mitochondria (PubMed:29165041). {ECO:0000269|PubMed:29165041}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q9Y4P1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y4P1-2; Sequence=VSP_013029, VSP_013034;
CC Name=3;
CC IsoId=Q9Y4P1-3; Sequence=VSP_013028, VSP_013031, VSP_013032;
CC Name=4;
CC IsoId=Q9Y4P1-4; Sequence=VSP_013028, VSP_013033;
CC Name=6;
CC IsoId=Q9Y4P1-6; Sequence=VSP_013034;
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with ATG8 family proteins MAP1LC3A, MAP1LC3B, MAP1LC3C and
CC GABARAPL1 (PubMed:28287329). Required for proteolytic activation and
CC delipidation of ATG8 proteins (PubMed:29458288, PubMed:28287329).
CC {ECO:0000269|PubMed:28287329, ECO:0000269|PubMed:29458288}.
CC -!- PTM: Phosphorylation at Ser-383 and Ser-392 promotes autophagy by
CC increasing protein delipidation activity without affecting proteolytic
CC activation of ATG8 proteins (PubMed:26378241). Phosphorylation at Ser-
CC 316 by ULK1 inhibits autophagy by decreasing both proteolytic
CC activation and delipidation activities (PubMed:28821708).
CC Phosphorylation at Ser-316 is dephosphorylated by protein phosphatase
CC 2A (PP2A) (PubMed:28821708). Phosphorylation at Ser-34 by AKT2 promotes
CC its hydrolase activity, leading to increased proteolytic activation and
CC delipidation of ATG8 family proteins (PubMed:30443548). Phosphorylation
CC at Ser-34 by AKT1 promotes mitochondrial localization and inhibition of
CC the F1F0-ATP synthase activity, leading to elevation of mitochondrial
CC reactive oxygen species (ROS) (PubMed:29165041).
CC {ECO:0000269|PubMed:26378241, ECO:0000269|PubMed:28821708,
CC ECO:0000269|PubMed:29165041, ECO:0000269|PubMed:30443548}.
CC -!- PTM: Ubiquitinated by RNF5, leading to its degradation by the
CC proteasome. {ECO:0000269|PubMed:23093945}.
CC -!- PTM: S-nitrosylation at Cys-189 and Cys-292 in response to high glucose
CC decreases both proteolytic activation and delipidation activities.
CC {ECO:0000269|PubMed:28633005}.
CC -!- PTM: O-glycosylated by OGT, leading to increase protease activity,
CC thereby promoting the proteolytic activation of ATG8 family proteins.
CC {ECO:0000269|PubMed:27527864}.
CC -!- PTM: Forms reversible intrachain disulfide bonds in response to
CC oxidative stress (PubMed:31880198). Forms interchain disulfide bonds,
CC leading to formation of homooligomers in response to oxidation
CC (PubMed:31880198). {ECO:0000269|PubMed:31880198}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
CC -!- CAUTION: A paper describing ATG4B tissue expression has been retracted,
CC due to concerns of image duplication in some of the figures.
CC {ECO:0000269|PubMed:12446702, ECO:0000305|PubMed:30808002}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA76787.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAC86110.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AJ504652; CAD43219.1; -; mRNA.
DR EMBL; AB066215; BAB83890.1; -; mRNA.
DR EMBL; AB023160; BAA76787.2; ALT_INIT; mRNA.
DR EMBL; AK027332; BAB55042.1; -; mRNA.
DR EMBL; AK027462; BAB55127.1; -; mRNA.
DR EMBL; AK027763; BAB55353.1; -; mRNA.
DR EMBL; AK125277; BAC86110.1; ALT_INIT; mRNA.
DR EMBL; AL080168; CAB45756.1; -; mRNA.
DR EMBL; AC133528; AAY14919.1; -; Genomic_DNA.
DR EMBL; BC000719; AAH00719.1; -; mRNA.
DR CCDS; CCDS46564.1; -. [Q9Y4P1-1]
DR CCDS; CCDS46565.1; -. [Q9Y4P1-6]
DR PIR; T12492; T12492.
DR RefSeq; NP_037457.3; NM_013325.4. [Q9Y4P1-1]
DR RefSeq; NP_847896.1; NM_178326.2. [Q9Y4P1-6]
DR PDB; 2CY7; X-ray; 1.90 A; A=1-393.
DR PDB; 2D1I; X-ray; 2.00 A; A/B=1-393.
DR PDB; 2Z0D; X-ray; 1.90 A; A=1-353.
DR PDB; 2Z0E; X-ray; 1.90 A; A=1-353.
DR PDB; 2ZZP; X-ray; 2.05 A; A=1-353.
DR PDB; 5LXH; X-ray; 1.58 A; E/F/G=384-393.
DR PDB; 5LXI; X-ray; 1.44 A; C/E=384-393.
DR PDBsum; 2CY7; -.
DR PDBsum; 2D1I; -.
DR PDBsum; 2Z0D; -.
DR PDBsum; 2Z0E; -.
DR PDBsum; 2ZZP; -.
DR PDBsum; 5LXH; -.
DR PDBsum; 5LXI; -.
DR AlphaFoldDB; Q9Y4P1; -.
DR SMR; Q9Y4P1; -.
DR BioGRID; 116801; 50.
DR IntAct; Q9Y4P1; 23.
DR MINT; Q9Y4P1; -.
DR STRING; 9606.ENSP00000384259; -.
DR BindingDB; Q9Y4P1; -.
DR ChEMBL; CHEMBL1741221; -.
DR MEROPS; C54.003; -.
DR TCDB; 9.A.15.2.1; the autophagy-related phagophore-formation transporter (apt) family.
DR GlyGen; Q9Y4P1; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9Y4P1; -.
DR PhosphoSitePlus; Q9Y4P1; -.
DR BioMuta; ATG4B; -.
DR DMDM; 296434400; -.
DR EPD; Q9Y4P1; -.
DR jPOST; Q9Y4P1; -.
DR MassIVE; Q9Y4P1; -.
DR MaxQB; Q9Y4P1; -.
DR PaxDb; Q9Y4P1; -.
DR PeptideAtlas; Q9Y4P1; -.
DR PRIDE; Q9Y4P1; -.
DR ProteomicsDB; 86230; -. [Q9Y4P1-1]
DR ProteomicsDB; 86231; -. [Q9Y4P1-2]
DR ProteomicsDB; 86232; -. [Q9Y4P1-3]
DR ProteomicsDB; 86233; -. [Q9Y4P1-4]
DR ProteomicsDB; 86234; -. [Q9Y4P1-6]
DR Antibodypedia; 12105; 728 antibodies from 41 providers.
DR DNASU; 23192; -.
DR Ensembl; ENST00000402096.5; ENSP00000384661.1; ENSG00000168397.17. [Q9Y4P1-4]
DR Ensembl; ENST00000404914.8; ENSP00000384259.3; ENSG00000168397.17. [Q9Y4P1-1]
DR Ensembl; ENST00000405546.7; ENSP00000383964.3; ENSG00000168397.17. [Q9Y4P1-6]
DR GeneID; 23192; -.
DR KEGG; hsa:23192; -.
DR MANE-Select; ENST00000404914.8; ENSP00000384259.3; NM_013325.5; NP_037457.3.
DR UCSC; uc002wbv.4; human. [Q9Y4P1-1]
DR CTD; 23192; -.
DR DisGeNET; 23192; -.
DR GeneCards; ATG4B; -.
DR HGNC; HGNC:20790; ATG4B.
DR HPA; ENSG00000168397; Low tissue specificity.
DR MIM; 611338; gene.
DR neXtProt; NX_Q9Y4P1; -.
DR OpenTargets; ENSG00000168397; -.
DR PharmGKB; PA134898340; -.
DR VEuPathDB; HostDB:ENSG00000168397; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_0_1_1; -.
DR InParanoid; Q9Y4P1; -.
DR OMA; CHTRRIR; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q9Y4P1; -.
DR TreeFam; TF314847; -.
DR PathwayCommons; Q9Y4P1; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR SABIO-RK; Q9Y4P1; -.
DR SignaLink; Q9Y4P1; -.
DR SIGNOR; Q9Y4P1; -.
DR BioGRID-ORCS; 23192; 14 hits in 1088 CRISPR screens.
DR ChiTaRS; ATG4B; human.
DR EvolutionaryTrace; Q9Y4P1; -.
DR GeneWiki; ATG4B; -.
DR GenomeRNAi; 23192; -.
DR Pharos; Q9Y4P1; Tchem.
DR PRO; PR:Q9Y4P1; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9Y4P1; protein.
DR Bgee; ENSG00000168397; Expressed in right hemisphere of cerebellum and 198 other tissues.
DR ExpressionAtlas; Q9Y4P1; baseline and differential.
DR Genevisible; Q9Y4P1; HS.
DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0019786; F:Atg8-specific peptidase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:Reactome.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0097110; F:scaffold protein binding; IPI:ARUK-UCL.
DR GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR GO; GO:0016237; P:lysosomal microautophagy; IDA:UniProtKB.
DR GO; GO:0016236; P:macroautophagy; TAS:Reactome.
DR GO; GO:0000423; P:mitophagy; IMP:UniProtKB.
DR GO; GO:0031173; P:otolith mineralization completed early in development; ISS:UniProtKB.
DR GO; GO:0051697; P:protein delipidation; IDA:UniProtKB.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR DisProt; DP01326; -.
DR IDEAL; IID00347; -.
DR InterPro; IPR032916; ATG4B_met.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR PANTHER; PTHR22624:SF39; PTHR22624:SF39; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Autophagy; Cytoplasm;
KW Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; Hydrolase; Isopeptide bond;
KW Mitochondrion; Phosphoprotein; Protease; Protein transport;
KW Reference proteome; S-nitrosylation; Thiol protease; Transport;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..393
FT /note="Cysteine protease ATG4B"
FT /id="PRO_0000215844"
FT MOTIF 388..391
FT /note="LIR"
FT /evidence="ECO:0000269|PubMed:28287329"
FT ACT_SITE 74
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:15169837,
FT ECO:0000269|PubMed:15187094, ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851, ECO:0000269|PubMed:20818167,
FT ECO:0000269|PubMed:26378241, ECO:0000269|PubMed:28821708,
FT ECO:0000269|PubMed:30443548"
FT ACT_SITE 278
FT /evidence="ECO:0000255, ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851"
FT ACT_SITE 280
FT /evidence="ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000269|Ref.10, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"
FT MOD_RES 34
FT /note="Phosphoserine; by PKB/AKT1 and PKB/AKT2"
FT /evidence="ECO:0000269|PubMed:29165041,
FT ECO:0000269|PubMed:30443548, ECO:0000269|PubMed:33607258"
FT MOD_RES 189
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:28633005"
FT MOD_RES 292
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:28633005"
FT MOD_RES 301
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:28633005"
FT MOD_RES 316
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:28821708"
FT MOD_RES 383
FT /note="Phosphoserine; by STK26"
FT /evidence="ECO:0000269|PubMed:26378241,
FT ECO:0000269|PubMed:29232556, ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 392
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:26378241"
FT DISULFID 292..361
FT /evidence="ECO:0000269|PubMed:31880198"
FT DISULFID 292
FT /note="Interchain (with C-361)"
FT /evidence="ECO:0000269|PubMed:31880198"
FT DISULFID 361
FT /note="Interchain (with C-292)"
FT /evidence="ECO:0000269|PubMed:31880198"
FT VAR_SEQ 1..74
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013028"
FT VAR_SEQ 1
FT /note="M -> MAHSVPSDSRTSRRPTTRPHAARGAPRGSRRPGRTPKWRLPRISARA
FT PYRLRRLRRHTYWPPRRPVAASRCWPVGATPLGSVGGRTGKM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013029"
FT VAR_SEQ 321..354
FT /note="FFCKTEDDFNDWCQQVKKLSLLGGALPMFELVEL -> KQGRLVRSLIPWAP
FT RPSSWCAAVLGAAVVMCGTP (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013031"
FT VAR_SEQ 355..393
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013032"
FT VAR_SEQ 369
FT /note="L -> LGESCQVQVGSLG (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013033"
FT VAR_SEQ 370..393
FT /note="DSSDVERLERFFDSEDEDFEILSL -> GESCQVQILLM (in isoform
FT 2 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_013034"
FT VARIANT 354
FT /note="L -> Q (in dbSNP:rs7601000)"
FT /evidence="ECO:0000269|PubMed:10231032,
FT ECO:0000269|PubMed:15169837, ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17974005"
FT /id="VAR_021486"
FT MUTAGEN 34
FT /note="S->A: Decreased phosphorylation by AKT2, leading to
FT reduced proteolytic activation of ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:30443548"
FT MUTAGEN 34
FT /note="S->D: Phospho-mimetic mutant; increased proteolytic
FT activation of ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:30443548"
FT MUTAGEN 74
FT /note="C->S: Complete loss of protease activity."
FT /evidence="ECO:0000269|PubMed:15169837,
FT ECO:0000269|PubMed:15187094, ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851, ECO:0000269|PubMed:20818167,
FT ECO:0000269|PubMed:26378241, ECO:0000269|PubMed:28821708,
FT ECO:0000269|PubMed:30443548"
FT MUTAGEN 78
FT /note="C->A: Reduces the redox sensitivity and retains
FT activity in presence of H(2)O(2)."
FT /evidence="ECO:0000269|PubMed:17347651"
FT MUTAGEN 78
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 89
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 121
FT /note="S->A: Decreased phosphorylation by AKT2; when
FT associated with A-262."
FT /evidence="ECO:0000269|PubMed:30443548"
FT MUTAGEN 142
FT /note="W->A: Strongly reduced protease activity."
FT /evidence="ECO:0000269|PubMed:16183633"
FT MUTAGEN 183
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 189
FT /note="C->S: Does not affect S-nitrosylation. Strongly
FT decreased S-nitrosylation, leading to increased hydrolase
FT activity and autophagic flux; when associated with S-292.
FT Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:28633005,
FT ECO:0000269|PubMed:31880198"
FT MUTAGEN 203
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 229
FT /note="R->A: Strongly reduced protease activity."
FT /evidence="ECO:0000269|PubMed:16183633"
FT MUTAGEN 246
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 262
FT /note="S->A: Decreased phosphorylation by AKT2; when
FT associated with A-121."
FT /evidence="ECO:0000269|PubMed:30443548"
FT MUTAGEN 278
FT /note="D->A: Complete loss of protease activity."
FT /evidence="ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851"
FT MUTAGEN 280
FT /note="H->A: Complete loss of protease activity."
FT /evidence="ECO:0000269|PubMed:16183633,
FT ECO:0000269|PubMed:16325851"
FT MUTAGEN 292
FT /note="C->S: Does not affect S-nitrosylation. Strongly
FT decreased S-nitrosylation, leading to increased hydrolase
FT activity and autophagic flux; when associated with S-189.
FT Reduced formation of intrachain and interchain disulfide
FT bonds in response to oxidation. Abolished formation of
FT disulfide bonds, leading to increased autophagy; when
FT associated with S-361."
FT /evidence="ECO:0000269|PubMed:28633005,
FT ECO:0000269|PubMed:31880198"
FT MUTAGEN 301
FT /note="C->S: Does not affect S-nitrosylation. Does not
FT affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:28633005,
FT ECO:0000269|PubMed:31880198"
FT MUTAGEN 306
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 316
FT /note="S->A: Abolished phosphorylation by ULK1; promotes
FT hydrolase activity, leading to increased proteolytic
FT activation and delipidation of ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:28821708"
FT MUTAGEN 316
FT /note="S->D: Phospho-mimetic mutant; reduced hydrolase
FT activity, leading to decreased proteolytic activation and
FT delipidation of ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:28821708"
FT MUTAGEN 323
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 333
FT /note="C->S: Does not affect formation of disulfide bonds."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 361
FT /note="C->S: Reduced formation of intrachain and interchain
FT disulfide bonds in response to oxidation. Abolished
FT formation of disulfide bonds, leading to increased
FT autophagy; when associated with S-292."
FT /evidence="ECO:0000269|PubMed:31880198"
FT MUTAGEN 383
FT /note="S->A: Decreased phosphorylation, leading to
FT decreased hydrolase activity and autophagic flux. Does not
FT affect interaction with ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:26378241,
FT ECO:0000269|PubMed:28287329, ECO:0000269|PubMed:29232556"
FT MUTAGEN 383
FT /note="S->E: Phospho-mimetic mutant; does not affect
FT interaction with ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:28287329"
FT MUTAGEN 388..391
FT /note="FEIL->AEIA: In 2mLIR; decreased interaction with
FT ATG8 family proteins MAP1LC3A, MAP1LC3B and MAP1LC3C.
FT Decreased ability to mediate delipidation of ATG8 proteins
FT conjugated to phosphatidylethanolamine (PE)."
FT /evidence="ECO:0000269|PubMed:28287329,
FT ECO:0000269|PubMed:29458288"
FT MUTAGEN 392
FT /note="S->A: Decreased phosphorylation, leading to
FT decreased hydrolase activity and autophagic flux. Does not
FT affect interaction with ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:26378241,
FT ECO:0000269|PubMed:28287329"
FT MUTAGEN 392
FT /note="S->E: Phospho-mimetic mutant; slightly increased
FT interaction with ATG8 family proteins."
FT /evidence="ECO:0000269|PubMed:28287329"
FT CONFLICT 136
FT /note="Missing (in Ref. 3; BAB83890)"
FT /evidence="ECO:0000305"
FT CONFLICT 188
FT /note="P -> L (in Ref. 6; BAB55127)"
FT /evidence="ECO:0000305"
FT CONFLICT 247
FT /note="F -> Y (in Ref. 6; BAB55353)"
FT /evidence="ECO:0000305"
FT CONFLICT 273
FT /note="E -> G (in Ref. 6; BAB55042)"
FT /evidence="ECO:0000305"
FT CONFLICT 312
FT /note="E -> N (in Ref. 3; BAB83890)"
FT /evidence="ECO:0000305"
FT HELIX 5..7
FT /evidence="ECO:0007829|PDB:2Z0E"
FT HELIX 10..13
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 14..18
FT /evidence="ECO:0007829|PDB:2Z0E"
FT STRAND 22..24
FT /evidence="ECO:0007829|PDB:2D1I"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 31..33
FT /evidence="ECO:0007829|PDB:2CY7"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 39..48
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 54..57
FT /evidence="ECO:0007829|PDB:2CY7"
FT TURN 61..64
FT /evidence="ECO:0007829|PDB:2CY7"
FT TURN 70..72
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 74..91
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 100..102
FT /evidence="ECO:0007829|PDB:2Z0E"
FT HELIX 106..113
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 116..118
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 125..133
FT /evidence="ECO:0007829|PDB:2CY7"
FT TURN 134..136
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 145..156
FT /evidence="ECO:0007829|PDB:2CY7"
FT TURN 160..162
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 165..168
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 176..183
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 184..186
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 222..229
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 232..234
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 237..239
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 240..246
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 252..257
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 264..270
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 273..277
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 281..284
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 290..292
FT /evidence="ECO:0007829|PDB:2D1I"
FT HELIX 297..299
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 306..309
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 310..312
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 315..325
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 326..341
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 349..353
FT /evidence="ECO:0007829|PDB:2CY7"
FT HELIX 371..376
FT /evidence="ECO:0007829|PDB:2CY7"
FT STRAND 388..390
FT /evidence="ECO:0007829|PDB:5LXH"
SQ SEQUENCE 393 AA; 44294 MW; F4ADB3192176E0E5 CRC64;
MDAATLTYDT LRFAEFEDFP ETSEPVWILG RKYSIFTEKD EILSDVASRL WFTYRKNFPA
IGGTGPTSDT GWGCMLRCGQ MIFAQALVCR HLGRDWRWTQ RKRQPDSYFS VLNAFIDRKD
SYYSIHQIAQ MGVGEGKSIG QWYGPNTVAQ VLKKLAVFDT WSSLAVHIAM DNTVVMEEIR
RLCRTSVPCA GATAFPADSD RHCNGFPAGA EVTNRPSPWR PLVLLIPLRL GLTDINEAYV
ETLKHCFMMP QSLGVIGGKP NSAHYFIGYV GEELIYLDPH TTQPAVEPTD GCFIPDESFH
CQHPPCRMSI AELDPSIAVG FFCKTEDDFN DWCQQVKKLS LLGGALPMFE LVELQPSHLA
CPDVLNLSLD SSDVERLERF FDSEDEDFEI LSL
