ATG4A_HUMAN
ID ATG4A_HUMAN Reviewed; 398 AA.
AC Q8WYN0; A6NCH2; B2RAZ7; D3DUY0; O95534; Q5JYY9; Q5JYZ0; Q86VE5; Q96KQ0;
AC Q96KQ1;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 1.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=Cysteine protease ATG4A {ECO:0000305};
DE EC=3.4.22.- {ECO:0000269|PubMed:21177865, ECO:0000269|PubMed:22302004};
DE AltName: Full=AUT-like 2 cysteine endopeptidase;
DE AltName: Full=Autophagy-related cysteine endopeptidase 2 {ECO:0000303|PubMed:12446702};
DE Short=Autophagin-2 {ECO:0000303|PubMed:12446702};
DE AltName: Full=Autophagy-related protein 4 homolog A {ECO:0000303|PubMed:12473658};
DE Short=HsAPG4A {ECO:0000303|PubMed:29458288};
DE Short=hAPG4A {ECO:0000303|PubMed:12473658};
GN Name=ATG4A {ECO:0000303|Ref.20, ECO:0000312|HGNC:HGNC:16489};
GN Synonyms=APG4A {ECO:0000303|PubMed:12473658},
GN AUTL2 {ECO:0000312|HGNC:HGNC:16489};
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=Ovary;
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), AND FUNCTION IN GABARAPL2; GABARAP
RP AND MAP1LC3 CLEAVAGE.
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 [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Prostate, and Testis;
RA Chen J.M., Barrett A.J.;
RT "Cloning and sequencing of a second human homologue of the yeast Apg4
RT cysteine endopeptidase involved in autophagy.";
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [7]
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Kidney, and 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 [9]
RP FUNCTION IN GABARAPL2 CLEAVAGE, AND ACTIVITY REGULATION.
RX PubMed=12473658; DOI=10.1074/jbc.m212108200;
RA Scherz-Shouval R., Sagiv Y., Shorer H., Elazar Z.;
RT "The COOH terminus of GATE-16, an intra-Golgi transport modulator, is
RT cleaved by the human cysteine protease HsApg4A.";
RL J. Biol. Chem. 278:14053-14058(2003).
RN [10]
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-81.
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 [11]
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 [12]
RP FUNCTION.
RX PubMed=21245471; DOI=10.1177/1087057110392996;
RA Shu C.W., Madiraju C., Zhai D., Welsh K., Diaz P., Sergienko E., Sano R.,
RA Reed J.C.;
RT "High-throughput fluorescence assay for small-molecule inhibitors of
RT autophagins/Atg4.";
RL J. Biomol. Screen. 16:174-182(2011).
RN [13]
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 [14]
RP MOTIF, AND DOMAIN.
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).
RN [15]
RP FUNCTION, AND CATALYTIC ACTIVITY.
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 [16]
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 [17]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF 390-GLU--VAL-398 AND SER-397.
RX PubMed=32732290; DOI=10.1074/jbc.ra120.013897;
RA Nguyen N., Olivas T.J., Mires A., Jin J., Yu S., Luan L., Nag S.,
RA Kauffman K.J., Melia T.J.;
RT "The insufficiency of ATG4A in macroautophagy.";
RL J. Biol. Chem. 295:13584-13600(2020).
RN [18]
RP FUNCTION, AND INTERACTION WITH ATG9A.
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 [19]
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 [20]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 23-359.
RA Walker J.R., Davis T., Mujib S., Butler-Cole C., Finerty P.J., Weigelt J.,
RA Sundstrom M., Arrowsmith C.H., Edwards A.M., Bochkarev A., Dhe-Paganon S.;
RT "Human cysteine protease ATG4A.";
RL Submitted (MAR-2007) to the PDB data bank.
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:12473658, PubMed:17347651,
CC PubMed:21177865, PubMed:21245471, PubMed:22302004, PubMed:32732290).
CC The protease activity is required for proteolytic activation of ATG8
CC family proteins: cleaves the C-terminal amino acid of ATG8 proteins to
CC reveal a C-terminal glycine (PubMed:15169837, PubMed:12473658,
CC PubMed:17347651, PubMed:21177865, PubMed:21245471, PubMed:22302004).
CC Exposure of the glycine at the C-terminus is essential for ATG8
CC proteins conjugation to phosphatidylethanolamine (PE) and insertion to
CC membranes, which is necessary for autophagy (PubMed:15169837,
CC PubMed:12473658, PubMed:17347651, PubMed:21177865, PubMed:21245471,
CC PubMed:22302004). Preferred substrate is GABARAPL2 followed by MAP1LC3A
CC and GABARAP (PubMed:15169837, PubMed:12473658, PubMed:17347651,
CC PubMed:21177865, PubMed:21245471, PubMed:22302004). Protease activity
CC is also required to counteract formation of high-molecular weight
CC conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-
CC like enzyme that removes ATG8 conjugated to other proteins, such as
CC ATG3 (PubMed:31315929, PubMed:33773106). In addition to the protease
CC activity, also mediates delipidation of ATG8 family proteins
CC (PubMed:29458288, PubMed:33909989). Catalyzes delipidation of PE-
CC conjugated forms of ATG8 proteins during macroautophagy
CC (PubMed:29458288, PubMed:33909989). Compared to ATG4B, the major
CC protein for proteolytic activation of ATG8 proteins, shows weaker
CC ability to cleave the C-terminal amino acid of ATG8 proteins, while it
CC displays stronger delipidation activity (PubMed:29458288). Involved in
CC phagophore growth during mitophagy independently of its protease
CC activity and of ATG8 proteins: acts by regulating ATG9A trafficking to
CC mitochondria and promoting phagophore-endoplasmic reticulum contacts
CC during the lipid transfer phase of mitophagy (PubMed:33773106).
CC {ECO:0000269|PubMed:12473658, ECO:0000269|PubMed:15169837,
CC ECO:0000269|PubMed:17347651, ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:21245471, ECO:0000269|PubMed:22302004,
CC ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:31315929,
CC ECO:0000269|PubMed:32732290, 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:29458288,
CC ECO:0000269|PubMed:33909989};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:33909989};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide (PubMed:12473658,
CC PubMed:21177865). Redox-regulated during autophagy since reducing
CC conditions activate ATG4A whereas an oxidizing environment such as the
CC presence of H(2)O(2) inhibits its activity (PubMed:17347651).
CC {ECO:0000269|PubMed:12473658, ECO:0000269|PubMed:17347651,
CC ECO:0000269|PubMed:21177865}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=33.9 uM for MAP1LC3B {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=20.8 uM for GABARAP {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=36.7 uM for GABARAPL1 {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC KM=15.7 uM for GABARAPL2 {ECO:0000269|PubMed:21177865,
CC ECO:0000269|PubMed:22302004};
CC -!- SUBUNIT: Interacts with ATG9A; the interaction is direct.
CC {ECO:0000269|PubMed:33773106}.
CC -!- INTERACTION:
CC Q8WYN0; Q8IVW4: CDKL3; NbExp=3; IntAct=EBI-3044060, EBI-3919850;
CC Q8WYN0; Q9H0R8: GABARAPL1; NbExp=6; IntAct=EBI-3044060, EBI-746969;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8WYN0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8WYN0-2; Sequence=VSP_013025;
CC Name=3;
CC IsoId=Q8WYN0-3; Sequence=VSP_025902;
CC Name=4;
CC IsoId=Q8WYN0-5; Sequence=VSP_030499;
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with the ATG8 family proteins (PubMed:28287329). Required
CC for proteolytic activation and delipidation of ATG8 proteins
CC (PubMed:32732290). {ECO:0000269|PubMed:28287329,
CC ECO:0000269|PubMed:32732290}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
CC -!- CAUTION: A paper describing ATG4D 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}.
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DR EMBL; AJ504651; CAD43218.1; -; mRNA.
DR EMBL; AB066214; BAB83889.1; -; mRNA.
DR EMBL; AJ320508; CAC69076.1; -; mRNA.
DR EMBL; AJ320509; CAC69077.1; -; mRNA.
DR EMBL; AK314429; BAG37044.1; -; mRNA.
DR EMBL; AL031177; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471120; EAX02689.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02691.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02693.1; -; Genomic_DNA.
DR EMBL; BC041862; AAH41862.1; -; mRNA.
DR EMBL; BC061696; AAH61696.1; -; mRNA.
DR CCDS; CCDS14538.1; -. [Q8WYN0-1]
DR CCDS; CCDS14539.1; -. [Q8WYN0-2]
DR RefSeq; NP_001308216.1; NM_001321287.1. [Q8WYN0-3]
DR RefSeq; NP_001308217.1; NM_001321288.1. [Q8WYN0-3]
DR RefSeq; NP_001308218.1; NM_001321289.1.
DR RefSeq; NP_443168.2; NM_052936.4. [Q8WYN0-1]
DR RefSeq; NP_840054.1; NM_178270.3. [Q8WYN0-2]
DR RefSeq; NP_840055.1; NM_178271.2. [Q8WYN0-3]
DR RefSeq; XP_011529144.1; XM_011530842.1. [Q8WYN0-3]
DR PDB; 2P82; X-ray; 2.10 A; A/B/C/D=23-359.
DR PDBsum; 2P82; -.
DR AlphaFoldDB; Q8WYN0; -.
DR SMR; Q8WYN0; -.
DR BioGRID; 125418; 29.
DR IntAct; Q8WYN0; 14.
DR MINT; Q8WYN0; -.
DR STRING; 9606.ENSP00000361306; -.
DR MEROPS; C54.002; -.
DR iPTMnet; Q8WYN0; -.
DR PhosphoSitePlus; Q8WYN0; -.
DR BioMuta; ATG4A; -.
DR DMDM; 61211859; -.
DR EPD; Q8WYN0; -.
DR jPOST; Q8WYN0; -.
DR MassIVE; Q8WYN0; -.
DR MaxQB; Q8WYN0; -.
DR PaxDb; Q8WYN0; -.
DR PeptideAtlas; Q8WYN0; -.
DR PRIDE; Q8WYN0; -.
DR ProteomicsDB; 75173; -. [Q8WYN0-1]
DR ProteomicsDB; 75174; -. [Q8WYN0-2]
DR ProteomicsDB; 75175; -. [Q8WYN0-3]
DR ProteomicsDB; 75176; -. [Q8WYN0-5]
DR Antibodypedia; 29398; 528 antibodies from 37 providers.
DR DNASU; 115201; -.
DR Ensembl; ENST00000345734.7; ENSP00000298131.5; ENSG00000101844.18. [Q8WYN0-2]
DR Ensembl; ENST00000372232.8; ENSP00000361306.3; ENSG00000101844.18. [Q8WYN0-1]
DR GeneID; 115201; -.
DR KEGG; hsa:115201; -.
DR MANE-Select; ENST00000372232.8; ENSP00000361306.3; NM_052936.5; NP_443168.2.
DR UCSC; uc004enr.4; human. [Q8WYN0-1]
DR CTD; 115201; -.
DR DisGeNET; 115201; -.
DR GeneCards; ATG4A; -.
DR HGNC; HGNC:16489; ATG4A.
DR HPA; ENSG00000101844; Low tissue specificity.
DR MIM; 300663; gene.
DR neXtProt; NX_Q8WYN0; -.
DR OpenTargets; ENSG00000101844; -.
DR PharmGKB; PA25184; -.
DR VEuPathDB; HostDB:ENSG00000101844; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_0_1_1; -.
DR InParanoid; Q8WYN0; -.
DR OMA; DIRTMAF; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q8WYN0; -.
DR TreeFam; TF314847; -.
DR PathwayCommons; Q8WYN0; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR SABIO-RK; Q8WYN0; -.
DR SignaLink; Q8WYN0; -.
DR BioGRID-ORCS; 115201; 16 hits in 703 CRISPR screens.
DR ChiTaRS; ATG4A; human.
DR EvolutionaryTrace; Q8WYN0; -.
DR GeneWiki; ATG4A; -.
DR GenomeRNAi; 115201; -.
DR Pharos; Q8WYN0; Tbio.
DR PRO; PR:Q8WYN0; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q8WYN0; protein.
DR Bgee; ENSG00000101844; Expressed in body of pancreas and 188 other tissues.
DR ExpressionAtlas; Q8WYN0; baseline and differential.
DR Genevisible; Q8WYN0; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0019786; F:Atg8-specific peptidase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0051697; P:protein delipidation; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR InterPro; IPR033474; ATG4A.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR PANTHER; PTHR22624:SF35; PTHR22624:SF35; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Autophagy; Cytoplasm; Hydrolase;
KW Lipid metabolism; Protease; Protein transport; Reference proteome;
KW Thiol protease; Transport; Ubl conjugation pathway.
FT CHAIN 1..398
FT /note="Cysteine protease ATG4A"
FT /id="PRO_0000215838"
FT MOTIF 393..396
FT /note="LIR"
FT /evidence="ECO:0000269|PubMed:28287329"
FT ACT_SITE 77
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 279
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 281
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT VAR_SEQ 1..77
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_025902"
FT VAR_SEQ 41..64
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_030499"
FT VAR_SEQ 211..272
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_013025"
FT MUTAGEN 81
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 390..398
FT /note="Missing: Decreased ability to mediate proteolytic
FT activation and delipidation of ATG8 proteins."
FT /evidence="ECO:0000269|PubMed:32732290"
FT MUTAGEN 397
FT /note="S->D: Phospho-mimetic mutant; slightly increased
FT delipidation of ATG8 proteins."
FT /evidence="ECO:0000269|PubMed:28287329"
FT CONFLICT 49
FT /note="I -> Y (in Ref. 8; AAH41862)"
FT /evidence="ECO:0000305"
FT CONFLICT 218
FT /note="S -> T (in Ref. 4; CAC69076/CAC69077)"
FT /evidence="ECO:0000305"
FT STRAND 28..31
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 34..37
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 38..41
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 42..50
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 57..61
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 64..67
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 73..75
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 77..94
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 110..116
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 119..121
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 128..136
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 137..139
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 148..159
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 163..165
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 168..171
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 176..178
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 179..186
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 223..230
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 238..240
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 241..249
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 253..260
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 263..271
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 274..278
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 282..285
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 298..300
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 307..310
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 311..313
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 316..326
FT /evidence="ECO:0007829|PDB:2P82"
FT HELIX 327..340
FT /evidence="ECO:0007829|PDB:2P82"
FT TURN 341..343
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 344..346
FT /evidence="ECO:0007829|PDB:2P82"
FT STRAND 348..354
FT /evidence="ECO:0007829|PDB:2P82"
SQ SEQUENCE 398 AA; 45378 MW; 3BE892E22E432151 CRC64;
MESVLSKYED QITIFTDYLE EYPDTDELVW ILGKQHLLKT EKSKLLSDIS ARLWFTYRRK
FSPIGGTGPS SDAGWGCMLR CGQMMLAQAL ICRHLGRDWS WEKQKEQPKE YQRILQCFLD
RKDCCYSIHQ MAQMGVGEGK SIGEWFGPNT VAQVLKKLAL FDEWNSLAVY VSMDNTVVIE
DIKKMCRVLP LSADTAGDRP PDSLTASNQS KGTSAYCSAW KPLLLIVPLR LGINQINPVY
VDAFKECFKM PQSLGALGGK PNNAYYFIGF LGDELIFLDP HTTQTFVDTE ENGTVNDQTF
HCLQSPQRMN ILNLDPSVAL GFFCKEEKDF DNWCSLVQKE ILKENLRMFE LVQKHPSHWP
PFVPPAKPEV TTTGAEFIDS TEQLEEFDLE EDFEILSV
