ID   ATG4_PICAN              Reviewed;         509 AA.
AC   A7KAI3;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   11-SEP-2007, sequence version 1.
DT   03-AUG-2022, entry version 39.
DE   RecName: Full=Probable cysteine protease ATG4;
DE            EC=3.4.22.-;
DE   AltName: Full=Autophagy-related protein 4;
GN   Name=ATG4;
OS   Pichia angusta (Yeast) (Hansenula polymorpha).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Pichiaceae; Ogataea.
OX   NCBI_TaxID=870730;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC   STRAIN=ATCC 34438 / CBS 4732 / DSM 70277 / JCM 3621 / NBRC 1476 / NRRL
RC   Y-5445;
RX   PubMed=17204848; DOI=10.4161/auto.3595;
RA   Meijer W.H., van der Klei I.J., Veenhuis M., Kiel J.A.K.W.;
RT   "ATG genes involved in non-selective autophagy are conserved from yeast to
RT   man, but the selective Cvt and pexophagy pathways also require organism-
RT   specific genes.";
RL   Autophagy 3:106-116(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 (PubMed:17204848). Required for
CC       selective autophagic degradation of the nucleus (nucleophagy) as well
CC       as for mitophagy which contributes to regulate mitochondrial quantity
CC       and quality by eliminating the mitochondria to a basal level to fulfill
CC       cellular energy requirements and preventing excess ROS production. The
CC       protease activity is required for proteolytic activation of ATG8:
CC       cleaves the C-terminal amino acid of ATG8 to reveal a C-terminal
CC       glycine. ATG8 ubiquitin-like activity requires the exposure of the
CC       glycine at the C-terminus for its conjugation to
CC       phosphatidylethanolamine (PE) and its insertion to membranes, which is
CC       necessary for autophagy. The ATG8-PE conjugate mediates tethering
CC       between adjacent membranes and stimulates membrane hemifusion, leading
CC       to expansion of the autophagosomal membrane during autophagy. In
CC       addition to the protease activity, also catalyzes deconjugation of PE-
CC       conjugated forms of ATG8 during macroautophagy: ATG8 delipidation is
CC       required to release the protein from membranes, which facilitates
CC       multiple events during macroautophagy, and especially for efficient
CC       autophagosome biogenesis, the assembly of ATG9-containing
CC       tubulovesicular clusters into phagophores/autophagosomes, and for the
CC       disassembly of PAS-associated ATG components. ATG8 delipidation by ATG4
CC       also recycles ATG8-PE generated on inappropriate membranes to maintain
CC       a reservoir of unlipidated ATG8 that is required for autophagosome
CC       formation at the PAS (By similarity). {ECO:0000250|UniProtKB:P53867,
CC       ECO:0000269|PubMed:17204848}.
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   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P53867}. Nucleus
CC       {ECO:0000250|UniProtKB:P53867}. Preautophagosomal structure
CC       {ECO:0000250|UniProtKB:P53867}.
CC   -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR   EMBL; EF102884; ABO31288.1; -; Genomic_DNA.
DR   AlphaFoldDB; A7KAI3; -.
DR   SMR; A7KAI3; -.
DR   MEROPS; C54.001; -.
DR   PRIDE; A7KAI3; -.
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:0006914; P:autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
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; Hydrolase; Nucleus; Protease; Protein transport;
KW   Thiol protease; Transport.
FT   CHAIN           1..509
FT                   /note="Probable cysteine protease ATG4"
FT                   /id="PRO_0000317842"
FT   ACT_SITE        130
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250|UniProtKB:P53867"
FT   ACT_SITE        305
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT   ACT_SITE        307
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
SQ   SEQUENCE   509 AA;  56839 MW;  868E0C4E6EC23602 CRC64;
     MASHSLNTLH TVFEYIWDRE LPNDDFTNTL TVLGRTYAPG PPPHQEKAPD LRTLFHKFKP
     DQAADTEASW PREFLRDVHS RIWLTYRSGF PLIKRAEDGP SPLSFGSLIR GTVDLATVTK
     GFTTDAGWGC MIRTSQSLLA NSLLQLRLGR GWRYDQTREC AKHAEIVSWF VDIPTAPFSI
     HNFVEQGANC AGKKPGEWFG PSAAARSIQV LCEANYDKTG LKVYFTASGD IYEDELFELA
     QQGAELRPVL ILAGIRLGVK NVNPLYWDFL KKTLGWPQSV GIAGGRPSSS HYFFGFQGDY
     LFYLDPHVPQ KALLIASEAP HESPDPNHYV EVESGLDLDS VHTNKIRKLH LDQMDPSMLV
     GLLVENRASY DALKHSINSH DQGSRFLNVY DSRPVLAAKS SGGLEESEFV DLGVLSMNEY
     DAIDDCDVGT CSALLRKERA FSHPVLVAMD PEEPEEIDAS IHFDKDASIL EKDPDRANET
     FEEIHVSETE SRFEPDEPVV VSHDSAAVM