ID ATG4_EREGS Reviewed; 521 AA.
AC Q75E61;
DT 26-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 27-MAR-2024, entry version 96.
DE RecName: Full=Probable cysteine protease ATG4;
DE EC=3.4.22.-;
DE AltName: Full=Autophagy-related protein 4;
GN Name=ATG4; OrderedLocusNames=ABL191W;
OS Eremothecium gossypii (strain ATCC 10895 / CBS 109.51 / FGSC 9923 / NRRL
OS Y-1056) (Yeast) (Ashbya gossypii).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Saccharomycetaceae; Eremothecium.
OX NCBI_TaxID=284811;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 10895 / CBS 109.51 / FGSC 9923 / NRRL Y-1056;
RX PubMed=15001715; DOI=10.1126/science.1095781;
RA Dietrich F.S., Voegeli S., Brachat S., Lerch A., Gates K., Steiner S.,
RA Mohr C., Poehlmann R., Luedi P., Choi S., Wing R.A., Flavier A.,
RA Gaffney T.D., Philippsen P.;
RT "The Ashbya gossypii genome as a tool for mapping the ancient Saccharomyces
RT cerevisiae genome.";
RL Science 304:304-307(2004).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=ATCC 10895 / CBS 109.51 / FGSC 9923 / NRRL Y-1056;
RX PubMed=23749448; DOI=10.1534/g3.112.002881;
RA Dietrich F.S., Voegeli S., Kuo S., Philippsen P.;
RT "Genomes of Ashbya fungi isolated from insects reveal four mating-type
RT loci, numerous translocations, lack of transposons, and distinct gene
RT duplications.";
RL G3 (Bethesda) 3:1225-1239(2013).
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 -!- 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; AE016815; AAS50580.1; -; Genomic_DNA.
DR RefSeq; NP_982756.1; NM_208109.1.
DR AlphaFoldDB; Q75E61; -.
DR SMR; Q75E61; -.
DR STRING; 284811.Q75E61; -.
DR MEROPS; C54.001; -.
DR EnsemblFungi; AAS50580; AAS50580; AGOS_ABL191W.
DR GeneID; 4618835; -.
DR KEGG; ago:AGOS_ABL191W; -.
DR eggNOG; KOG2674; Eukaryota.
DR HOGENOM; CLU_021259_5_3_1; -.
DR InParanoid; Q75E61; -.
DR OMA; CKINESE; -.
DR OrthoDB; 276806at2759; -.
DR Proteomes; UP000000591; Chromosome II.
DR GO; GO:0005829; C:cytosol; IEA:EnsemblFungi.
DR GO; GO:0005739; C:mitochondrion; IEA:EnsemblFungi.
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:0019786; F:protein-phosphatidylethanolamide deconjugating activity; IEA:EnsemblFungi.
DR GO; GO:0000045; P:autophagosome assembly; IEA:EnsemblFungi.
DR GO; GO:0032258; P:cytoplasm to vacuole transport by the Cvt pathway; IEA:EnsemblFungi.
DR GO; GO:0034727; P:piecemeal microautophagy of the nucleus; IEA:EnsemblFungi.
DR GO; GO:0006612; P:protein targeting to membrane; IEA:EnsemblFungi.
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 InterPro; IPR046792; Peptidase_C54_cat.
DR PANTHER; PTHR22624:SF49; CYSTEINE PROTEASE; 1.
DR PANTHER; PTHR22624; CYSTEINE PROTEASE ATG4; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; Cysteine proteinases; 1.
PE 3: Inferred from homology;
KW Autophagy; Cytoplasm; Hydrolase; Nucleus; Protease; Protein transport;
KW Reference proteome; Thiol protease; Transport.
FT CHAIN 1..521
FT /note="Probable cysteine protease ATG4"
FT /id="PRO_0000215857"
FT ACT_SITE 177
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 352
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 354
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
SQ SEQUENCE 521 AA; 59038 MW; 931657B31671ED91 CRC64;
MGFLIAYVFN LSPCSGDEMF ETIGLAIIHF EGLNTNRVSK CNQNWHQESK QVAMELIQKV
SQGLWELENC DTVNSVVVLG KEYPPVPEQR QEERHENGVN MFQHIFTRQG RWNEEFLADV
HTRLHFTYRT RFVPIPRHPN GPSPMSISVM LRDNPLNVIE NVLNNPDCFQ TDIGWGCMIR
TGQSLLANAL QRACLGRDFR IDDNAANEHE LRIIKWFEDD PKYPFSLHKF VQEGFSLSGK
KPGEWFGPSA TSRSIQALVA KFPACGIAHC VISTDSGDVY MDEVEPLFRA DPSAAVLLLL
CVRLGVDVVN EVYWEHIRHI LSSEHSVGIA GGRPSSSLYF FGYQDEHLFY LDPHKPQLNL
ASYQQDLDLF RSVHTQRFNK VHMSDIDPSM LIGILLNGKD DWQLWQQHIA SSQIIHLSDS
KPVDLMLDHQ LESAILGDRY LSEDGQGPSS KVDTGDYIDV GSFVPCTDSS CKINESEDEY
QDVKCKNQRI VVVGETTTNG SPEVEVEKVL VEKETIPVRS K
//
