ATG4_YEAS7
ID ATG4_YEAS7 Reviewed; 494 AA.
AC A6ZRL7;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 11-SEP-2007, sequence version 1.
DT 03-AUG-2022, entry version 60.
DE RecName: Full=Cysteine protease ATG4;
DE EC=3.4.22.-;
DE AltName: Full=Autophagy-related protein 4;
GN Name=ATG4; Synonyms=APG4, AUT2; ORFNames=SCY_4578;
OS Saccharomyces cerevisiae (strain YJM789) (Baker's yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX NCBI_TaxID=307796;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=YJM789;
RX PubMed=17652520; DOI=10.1073/pnas.0701291104;
RA Wei W., McCusker J.H., Hyman R.W., Jones T., Ning Y., Cao Z., Gu Z.,
RA Bruno D., Miranda M., Nguyen M., Wilhelmy J., Komp C., Tamse R., Wang X.,
RA Jia P., Luedi P., Oefner P.J., David L., Dietrich F.S., Li Y., Davis R.W.,
RA Steinmetz L.M.;
RT "Genome sequencing and comparative analysis of Saccharomyces cerevisiae
RT strain YJM789.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:12825-12830(2007).
CC -!- FUNCTION: Cysteine protease that plays a key role in cytoplasm to
CC vacuole transport (Cvt) and autophagy by mediating both proteolytic
CC activation and delipidation of ATG8. Required for selective autophagic
CC degradation of the nucleus (nucleophagy) as well as for mitophagy which
CC contributes to regulate mitochondrial quantity and quality by
CC eliminating the mitochondria to a basal level to fulfill cellular
CC energy requirements and preventing excess ROS production. The protease
CC activity is required for proteolytic activation of ATG8: cleaves the C-
CC terminal amino acid of ATG8 to reveal a C-terminal glycine. ATG8
CC ubiquitin-like activity requires the exposure of the glycine at the C-
CC terminus for its conjugation to phosphatidylethanolamine (PE) and its
CC insertion to membranes, which is necessary for autophagy. The ATG8-PE
CC conjugate mediates tethering between adjacent membranes and stimulates
CC membrane hemifusion, leading to expansion of the autophagosomal
CC membrane during autophagy. In addition to the protease activity, also
CC catalyzes deconjugation of PE-conjugated forms of ATG8 during
CC macroautophagy: ATG8 delipidation is required to release the protein
CC from membranes, which facilitates multiple events during
CC macroautophagy, and especially for efficient autophagosome biogenesis,
CC the assembly of ATG9-containing tubulovesicular clusters into
CC phagophores/autophagosomes, and for the disassembly of PAS-associated
CC ATG components. ATG8 delipidation by ATG4 also recycles ATG8-PE
CC generated on inappropriate membranes to maintain a reservoir of
CC unlipidated ATG8 that is required for autophagosome formation at the
CC PAS. {ECO:0000250|UniProtKB:P53867}.
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:P53867};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:P53867};
CC -!- SUBUNIT: Interacts with ATG8. Interacts with TUB1 and TUB2.
CC {ECO:0000250|UniProtKB:P53867}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P53867}. Nucleus
CC {ECO:0000250|UniProtKB:P53867}. Preautophagosomal structure
CC {ECO:0000250|UniProtKB:P53867}.
CC -!- DOMAIN: The APEAR motif (ATG8-PE association region) plays a key role
CC in ATG4 recruitment to autophagosomal membranes and ATG8 deconjugation.
CC The LIR (LC3-interacting region act cooperatively) and APEAR motifs for
CC the interaction with ATG8. {ECO:0000250|UniProtKB:P53867}.
CC -!- PTM: Phosphorylation at Ser-307 by ATG1 inhibits autophagy: it takes
CC place on autophagosome membranes and decreases its interaction with
CC ATG8, thereby impairing deconjugation of PE-conjugated forms of ATG8.
CC {ECO:0000250|UniProtKB:P53867}.
CC -!- PTM: Formation of a disulfide bond between Cys-338 and Cys-394 leads to
CC reduced autophagy. The disulfide bond is reduced by thioredoxin.
CC {ECO:0000250|UniProtKB:P53867}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; AAFW02000067; EDN62599.1; -; Genomic_DNA.
DR AlphaFoldDB; A6ZRL7; -.
DR SMR; A6ZRL7; -.
DR MEROPS; C54.001; -.
DR PRIDE; A6ZRL7; -.
DR EnsemblFungi; EDN62599; EDN62599; SCY_4578.
DR HOGENOM; CLU_021259_5_3_1; -.
DR Proteomes; UP000007060; Unassembled WGS sequence.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0000045; P:autophagosome assembly; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; ISS:UniProtKB.
DR GO; GO:0006612; P:protein targeting to membrane; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 3: Inferred from homology;
KW Autophagy; Cytoplasm; Disulfide bond; Hydrolase; Isopeptide bond; Nucleus;
KW Phosphoprotein; Protease; Protein transport; Thiol protease; Transport.
FT CHAIN 1..494
FT /note="Cysteine protease ATG4"
FT /id="PRO_0000317847"
FT MOTIF 102..105
FT /note="APEAR"
FT /evidence="ECO:0000250|UniProtKB:P53867"
FT MOTIF 424..427
FT /note="LIR"
FT /evidence="ECO:0000250|UniProtKB:P53867"
FT ACT_SITE 147
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 322
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 324
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P53867"
FT MOD_RES 488
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P53867"
FT DISULFID 338..394
FT /evidence="ECO:0000250|UniProtKB:P53867"
SQ SEQUENCE 494 AA; 55143 MW; E68ABCA662A28C32 CRC64;
MQRWLQLWKM DLVQKVSHGV FEGSSEEPAA LMNHDYIVLG EVYPERDEES GAEQCEQDCR
YRGEAVSDGF LSSLFGREIS SYTKEFLLDV QSRVNFTYRT RFVPIARAPD GPSPLSLNLL
VRTNPISTIE DYIANPDCFN TDIGWGCMIR TGQSLLGNAL QILHLGRDFR VNGNESLERE
SKFVNWFNDT PEAPFSLHNF VSAGTELSDK RPGEWFGPAA TARSIQSLIY GFPECGIDDC
IVSVSSGDIY ENEVEKVFAE NPNSRILFLL GVKLGINAVN ESYRESICGI LSSTQSVGIA
GGRPSSSLYF FGYQGNEFLH FDPHIPQPAV EDSFVESCHT SKFGKLQLSE MDPSMLIGIL
IKGEKDWQQW KLEVAESAII NVLAKRMDDF DVSCSMDDVE SVSSNSMKKD ASNNENLGVL
EGDYVDIGAI FPHTTNTEDV DEYDCFQDIH CKKQKIVVMG NTHTVNANLT DYEVEGVLVE
KETVGIHSPI DEKC
