ATG4C_MOUSE
ID ATG4C_MOUSE Reviewed; 458 AA.
AC Q811C2; B1ASJ9; Q6PD25;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Cysteine protease ATG4C {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q96DT6};
DE AltName: Full=AUT-like 3 cysteine endopeptidase;
DE AltName: Full=Autophagy-related cysteine endopeptidase 3 {ECO:0000303|PubMed:12446702};
DE Short=Autophagin-3 {ECO:0000303|PubMed:12446702};
DE AltName: Full=Autophagy-related protein 4 homolog C {ECO:0000303|PubMed:17442669};
GN Name=Atg4c {ECO:0000303|PubMed:17442669, ECO:0000312|MGI:MGI:2651854};
GN Synonyms=Apg4c, Autl3;
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 TISSUE=Brain;
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 GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
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 [5]
RP RETRACTED PAPER.
RX PubMed=17442669; DOI=10.1074/jbc.m701194200;
RA Marino G., Salvador-Montoliu N., Fueyo A., Knecht E., Mizushima N.,
RA Lopez-Otin C.;
RT "Tissue-specific autophagy alterations and increased tumorigenesis in mice
RT deficient in Atg4C/autophagin-3.";
RL J. Biol. Chem. 282:18573-18583(2007).
RN [6]
RP RETRACTION NOTICE OF PUBMED:17442669.
RX PubMed=30808006; DOI=10.1074/jbc.w118.007329;
RA Marino G., Salvador-Montoliu N., Fueyo A., Knecht E., Mizushima N.,
RA Lopez-Otin C.;
RL J. Biol. Chem. 294:1435-1435(2019).
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 MAP1LC3 and GABARAPL2, to reveal a C-terminal glycine (By
CC similarity). Exposure of the glycine at the C-terminus is essential for
CC ATG8 proteins conjugation to phosphatidylethanolamine (PE) and
CC insertion to membranes, which is necessary for autophagy (By
CC similarity). In addition to the protease activity, also mediates
CC delipidation of ATG8 family proteins. Catalyzes delipidation of PE-
CC conjugated forms of ATG8 proteins during macroautophagy. Compared to
CC ATG4B, the major protein for proteolytic activation of ATG8 proteins,
CC shows weaker ability to cleave the C-terminal amino acid of ATG8
CC proteins, while it displays stronger delipidation activity. In contrast
CC to other members of the family, weakly or not involved in phagophore
CC growth during mitophagy (By similarity). {ECO:0000250|UniProtKB:Q96DT6,
CC ECO:0000250|UniProtKB:Q9Y4P1}.
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:Q96DT6};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q96DT6};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide.
CC {ECO:0000250|UniProtKB:Q96DT6}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
CC -!- CAUTION: Was reported that this protein is required for a proper
CC autophagic response under stressful conditions such as prolonged
CC starvation, based on experiments conducted on cells or mice claimed to
CC have null alleles (PubMed:17442669). However, this paper has been
CC retracted because of aberrations in the relevant figure
CC (PubMed:30808006). Nevertheless, a separate experiment in the same
CC paper suggests that the alleles are null and so the inferred function
CC may be true. {ECO:0000269|PubMed:17442669, ECO:0000269|PubMed:30808006,
CC ECO:0000305}.
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DR EMBL; AJ312233; CAC85555.1; -; Genomic_DNA.
DR EMBL; AL627166; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC058981; AAH58981.1; -; mRNA.
DR CCDS; CCDS18382.1; -.
DR RefSeq; NP_001139439.1; NM_001145967.1.
DR RefSeq; NP_778194.3; NM_175029.3.
DR AlphaFoldDB; Q811C2; -.
DR SMR; Q811C2; -.
DR STRING; 10090.ENSMUSP00000030279; -.
DR MEROPS; C54.004; -.
DR iPTMnet; Q811C2; -.
DR PhosphoSitePlus; Q811C2; -.
DR MaxQB; Q811C2; -.
DR PaxDb; Q811C2; -.
DR PeptideAtlas; Q811C2; -.
DR PRIDE; Q811C2; -.
DR ProteomicsDB; 265148; -.
DR Antibodypedia; 1971; 613 antibodies from 38 providers.
DR DNASU; 242557; -.
DR Ensembl; ENSMUST00000030279; ENSMUSP00000030279; ENSMUSG00000028550.
DR Ensembl; ENSMUST00000180278; ENSMUSP00000137035; ENSMUSG00000028550.
DR GeneID; 242557; -.
DR KEGG; mmu:242557; -.
DR UCSC; uc008tut.1; mouse.
DR CTD; 84938; -.
DR MGI; MGI:2651854; Atg4c.
DR VEuPathDB; HostDB:ENSMUSG00000028550; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_3_2_1; -.
DR InParanoid; Q811C2; -.
DR OMA; KMAGDWY; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q811C2; -.
DR TreeFam; TF314847; -.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR BioGRID-ORCS; 242557; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Atg4c; mouse.
DR PRO; PR:Q811C2; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q811C2; protein.
DR Bgee; ENSMUSG00000028550; Expressed in parotid gland and 222 other tissues.
DR Genevisible; Q811C2; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
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: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; IPR032915; ATG4C.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR PANTHER; PTHR22624:SF38; PTHR22624:SF38; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Autophagy; Cytoplasm; Hydrolase; Phosphoprotein; Protease;
KW Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..458
FT /note="Cysteine protease ATG4C"
FT /id="PRO_0000215850"
FT ACT_SITE 111
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 345
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 347
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q96DT6"
FT MOD_RES 451
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96DT6"
FT MOD_RES 452
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q96DT6"
FT CONFLICT 87
FT /note="I -> L (in Ref. 4; AAH58981)"
FT /evidence="ECO:0000305"
FT CONFLICT 190
FT /note="A -> T (in Ref. 1; CAC85555)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 458 AA; 52056 MW; E9F1C1A697CA4978 CRC64;
MEASGTDEVD KLKTKFISAW NNMKYSWVLK TKTYFSRNSP VLLLGKCYHF KYEDESKMLP
ARSGCAIEDH VIAGNVEEFR KDFISRIWLT YREEFPQIEA SALTTDCGWG CTLRTGQMLL
AQGLILHFLG RAWTWPDALH IENADSDSWT SNTVKKFTAS FEASLSGDRE LRTPAVSLKE
TSGKCPDDHA VRNEAYHRKI ISWFGDSPVA VFGLHRLIEF GKKSGKKAGD WYGPAVVAHI
LRKAVEEARH PDLQGLTIYV AQDCTVYNSD VIDKQTDSVT AGDARDKAVI ILVPVRLGGE
RTNTDYLEFV KGVLSLEYCV GIIGGKPKQS YYFAGFQDDS LIYMDPHYCQ SFVDVSIKDF
PLETFHCPSP KKMSFRKMDP SCTIGFYCRN VQDFERASEE ITKMLKISSK EKYPLFTFVN
GHSKDFDFTS TAASEEDLFS EDERKNFKRF STEEFVLL
