ATG4A_MOUSE
ID ATG4A_MOUSE Reviewed; 396 AA.
AC Q8C9S8; Q811B8;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Cysteine protease ATG4A {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q8WYN0};
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:0000250|UniProtKB:Q8WYN0};
GN Name=Atg4a {ECO:0000312|MGI:MGI:2147903};
GN Synonyms=Apg4a {ECO:0000250|UniProtKB:Q8WYN0},
GN Autl2 {ECO:0000312|MGI:MGI:2147903};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND RETRACTED PAPER.
RC STRAIN=C57BL/6J;
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 [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
CC -!- FUNCTION: Cysteine protease that plays a key role in autophagy by
CC mediating both proteolytic activation and delipidation of ATG8 family
CC proteins. The protease activity is required for proteolytic activation
CC of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8
CC proteins to reveal a C-terminal glycine. Exposure of the glycine at the
CC C-terminus is essential for ATG8 proteins conjugation to
CC phosphatidylethanolamine (PE) and insertion to membranes, which is
CC necessary for autophagy. Preferred substrate is GABARAPL2 followed by
CC MAP1LC3A and GABARAP. Protease activity is also required to counteract
CC formation of high-molecular weight conjugates of ATG8 proteins
CC (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8
CC conjugated to other proteins, such as ATG3. In addition to the protease
CC activity, also mediates delipidation of ATG8 family proteins. Catalyzes
CC delipidation of PE-conjugated forms of ATG8 proteins during
CC macroautophagy. Compared to ATG4B, the major protein for proteolytic
CC activation of ATG8 proteins, shows weaker ability to cleave the C-
CC terminal amino acid of ATG8 proteins, while it displays stronger
CC delipidation activity. Involved in phagophore growth during mitophagy
CC independently of its protease activity and of ATG8 proteins: acts by
CC regulating ATG9A trafficking to mitochondria and promoting phagophore-
CC endoplasmic reticulum contacts during the lipid transfer phase of
CC mitophagy. {ECO:0000250|UniProtKB:Q8WYN0}.
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:0000250|UniProtKB:Q8WYN0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q8WYN0};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide. Redox-regulated
CC during autophagy since reducing conditions activate ATG4A whereas an
CC oxidizing environment such as the presence of H(2)O(2) inhibits its
CC activity. {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SUBUNIT: Interacts with ATG9A; the interaction is direct.
CC {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with the ATG8 family proteins. Required for proteolytic
CC activation and delipidation of ATG8 proteins.
CC {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; AJ504654; CAD43221.1; -; mRNA.
DR EMBL; AK041379; BAC30924.1; -; mRNA.
DR CCDS; CCDS85810.1; -.
DR RefSeq; NP_777364.3; NM_174875.3.
DR AlphaFoldDB; Q8C9S8; -.
DR SMR; Q8C9S8; -.
DR STRING; 10090.ENSMUSP00000108595; -.
DR MEROPS; C54.002; -.
DR PhosphoSitePlus; Q8C9S8; -.
DR EPD; Q8C9S8; -.
DR MaxQB; Q8C9S8; -.
DR PaxDb; Q8C9S8; -.
DR PRIDE; Q8C9S8; -.
DR ProteomicsDB; 277088; -.
DR DNASU; 666468; -.
DR Ensembl; ENSMUST00000112971; ENSMUSP00000108595; ENSMUSG00000079418.
DR GeneID; 666468; -.
DR KEGG; mmu:666468; -.
DR UCSC; uc029unx.1; mouse.
DR CTD; 115201; -.
DR MGI; MGI:2147903; Atg4a.
DR VEuPathDB; HostDB:ENSMUSG00000079418; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_0_1_1; -.
DR InParanoid; Q8C9S8; -.
DR OMA; NREHHEA; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q8C9S8; -.
DR TreeFam; TF314847; -.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR BioGRID-ORCS; 666468; 2 hits in 52 CRISPR screens.
DR PRO; PR:Q8C9S8; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q8C9S8; protein.
DR Bgee; ENSMUSG00000079418; Expressed in bone marrow and 60 other tissues.
DR ExpressionAtlas; Q8C9S8; baseline and differential.
DR Genevisible; Q8C9S8; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0019786; F:Atg8-specific peptidase activity; ISS:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0008234; F:cysteine-type peptidase activity; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; ISS:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0051697; P:protein delipidation; ISS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
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 2: Evidence at transcript level;
KW Autophagy; Cytoplasm; Hydrolase; Lipid metabolism; Protease;
KW Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..396
FT /note="Cysteine protease ATG4A"
FT /id="PRO_0000215839"
FT MOTIF 390..393
FT /note="LIR"
FT /evidence="ECO:0000250|UniProtKB:Q8WYN0"
FT ACT_SITE 77
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 276
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 278
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT CONFLICT 38
FT /note="L -> F (in Ref. 1; CAD43221)"
FT /evidence="ECO:0000305"
FT CONFLICT 159
FT /note="A -> T (in Ref. 1; CAD43221)"
FT /evidence="ECO:0000305"
FT CONFLICT 171
FT /note="V -> D (in Ref. 3; BAC30924)"
FT /evidence="ECO:0000305"
FT CONFLICT 203
FT /note="A -> V (in Ref. 1; CAD43221)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 396 AA; 45095 MW; 99196D35E6856594 CRC64;
MESVMSKYEN QILIFPDYLE EFPDTDELVW ILGKQHPLKT EKSKLLSDIS ARLWFTYRRK
FSPIGGTGPS SDAGWGCMLR CGQMMLAQAL ICRHLGRDWN WERQKEQPKE YQRILQCFLD
RKDCCYSIHQ MAQMGVGEGK SIGEWFGPNT VAQVIKKLAL FDEWNSLAVY VSMDNTVVIE
DIKKMCCVLP VGAADPAGDF LTASNQSRDT SVPCSAWKPL LLIVPLRLGI NQINPVYVEA
FKECFKMPQS LGALGGKPNN AYYFIGFLGD ELIFLDPHTT QTFVDIEESG LVDDQTFHCL
QSPQRMSILN LDPSVALGFF CKEEKDFDNW CSLVQKEILK ENLRMFELVQ KHPSHWPPFV
PPAKPEVTTT GAEFIESTEQ LEDFELEEDF EILSVG
