ATG4D_PIG
ID ATG4D_PIG Reviewed; 469 AA.
AC Q684M2;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 78.
DE RecName: Full=Cysteine protease ATG4D {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q86TL0};
DE AltName: Full=Autophagy-related protein 4 homolog D {ECO:0000303|Ref.1};
DE Short=Autophagin-4 {ECO:0000250|UniProtKB:Q86TL0};
DE Contains:
DE RecName: Full=Cysteine protease ATG4D, mitochondrial {ECO:0000250|UniProtKB:Q86TL0};
GN Name=ATG4D {ECO:0000250|UniProtKB:Q86TL0};
GN Synonyms=APG4D {ECO:0000303|Ref.1};
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Leeb T.;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: [Cysteine protease ATG4D]: Cysteine protease that plays a key
CC role in autophagy by mediating both proteolytic activation and
CC delipidation of ATG8 family proteins. The protease activity is required
CC for proteolytic activation of ATG8 family proteins: cleaves the C-
CC terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, to reveal a
CC C-terminal glycine (By similarity). Exposure of the glycine at the C-
CC terminus is essential for ATG8 proteins conjugation to
CC phosphatidylethanolamine (PE) and insertion to membranes, which is
CC necessary for autophagy (By similarity). 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. Also involved in non-canonical autophagy, a parallel
CC pathway involving conjugation of ATG8 proteins to single membranes at
CC endolysosomal compartments, by catalyzing delipidation of ATG8 proteins
CC conjugated to phosphatidylserine (PS) (By similarity). ATG4D plays a
CC role in the autophagy-mediated neuronal homeostasis in the central
CC nervous system. Compared to other members of the family (ATG4A, ATG4B
CC or ATG4C), constitutes the major protein for the delipidation activity,
CC while it promotes weak proteolytic activation of ATG8 proteins (By
CC similarity). 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 (By similarity). {ECO:0000250|UniProtKB:Q86TL0,
CC ECO:0000250|UniProtKB:Q8BGV9, ECO:0000250|UniProtKB:Q9Y4P1}.
CC -!- FUNCTION: [Cysteine protease ATG4D, mitochondrial]: Plays a role as an
CC autophagy regulator that links mitochondrial dysfunction with
CC apoptosis. The mitochondrial import of ATG4D during cellular stress and
CC differentiation may play important roles in the regulation of
CC mitochondrial physiology, ROS, mitophagy and cell viability.
CC {ECO:0000250|UniProtKB:Q86TL0}.
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:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylserine +
CC H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-
CC glycero-3-phospho-L-serine; Xref=Rhea:RHEA:67576, Rhea:RHEA-
CC COMP:17324, Rhea:RHEA-COMP:17326, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57262, ChEBI:CHEBI:172940, ChEBI:CHEBI:172942;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67577;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D, mitochondrial]:
CC Cytoplasm {ECO:0000250|UniProtKB:Q86TL0}. Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q86TL0}. Note=Imported into mitochondrial matrix
CC after cleavage by CASP3 during oxidative stress and cell death.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DOMAIN: The cryptic mitochondrial transit peptide is revealed after
CC cleavage by caspase upon oxidative stress and cell death. It acts then
CC as a functional transit peptide, and allows the import of the cleaved
CC protein into the mitochondria. {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- PTM: Cleaved by CASP3 during apoptosis which leads to increased
CC activity. The cleavage by CASP3 reveals a cryptic mitochondrial
CC targeting sequence immediately downstream of their canonical caspase
CC cleavage sites which leads to mitochondrial import of the protein.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; AJ632303; CAG15153.1; -; Genomic_DNA.
DR RefSeq; NP_001116551.1; NM_001123079.1.
DR AlphaFoldDB; Q684M2; -.
DR SMR; Q684M2; -.
DR STRING; 9823.ENSSSCP00000014504; -.
DR MEROPS; C54.005; -.
DR PaxDb; Q684M2; -.
DR Ensembl; ENSSSCT00030037698; ENSSSCP00030017286; ENSSSCG00030026949.
DR GeneID; 100141400; -.
DR KEGG; ssc:100141400; -.
DR CTD; 84971; -.
DR eggNOG; KOG2674; Eukaryota.
DR InParanoid; Q684M2; -.
DR OrthoDB; 431748at2759; -.
DR Reactome; R-SSC-1632852; Macroautophagy.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0008234; F:cysteine-type peptidase activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006914; P:autophagy; ISS:UniProtKB.
DR GO; GO:0000423; P:mitophagy; ISS:UniProtKB.
DR GO; GO:0051697; P:protein delipidation; ISS:UniProtKB.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; ISS:UniProtKB.
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 Apoptosis; Autophagy; Cytoplasm; Hydrolase; Mitochondrion; Phosphoprotein;
KW Protease; Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..469
FT /note="Cysteine protease ATG4D"
FT /id="PRO_0000215855"
FT CHAIN 63..469
FT /note="Cysteine protease ATG4D, mitochondrial"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT /id="PRO_0000423410"
FT REGION 1..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 63..102
FT /note="Cryptic mitochondrial signal peptide"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT ACT_SITE 143
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 351
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 353
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT SITE 62..63
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT MOD_RES 462
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
SQ SEQUENCE 469 AA; 52429 MW; 424E114BC984929E CRC64;
MNSVSPAAAQ YQSGSPEDAR RPEGRRPRGP RTPDPNSLGP SGASGPALAS PGVGPGEPDE
VDKFKAKFLT AWNNVKYGWA VKSRTSFSKI SSVHLCGRRY RFEGEGDIQR FQRDFVSRLW
LTYRRDFPPL AGGCLTSDCG WGCMLRSGQM MLAQGLLLHF LPRDWTWSQG VGLGPPESSP
NRYRGPAHWM PPHWVQAAPE LEQERRHRQI VSWFADHPRA PFGLHRLVEL GQSSGKKAGD
WYGPSLVAHI LRKAVESCSE VTRLVVYVSQ DCTVYKADVA RLVARPDPTA EWKAVVILVP
VRLGGETLNP VYVPCVKELL RSELCLGIMG GKPRHSLYFI GYQDDFLLYL DPHYCQPTVD
VSQADFPLES FHCTSPRKMA FTKMDPSCTV GFYAGDRKEF ETLCSELTRV LSSSSATERY
PMFTLVEGHA QDHSLDDLCS QPSQPTLRLP RTGRLLKAKR PSSEDFVFL
