ATG4A_PONAB
ID ATG4A_PONAB Reviewed; 398 AA.
AC Q5R699;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 68.
DE RecName: Full=Cysteine protease ATG4A {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q8WYN0};
DE AltName: Full=Autophagy-related protein 4 homolog A {ECO:0000250|UniProtKB:Q8WYN0};
GN Name=ATG4A {ECO:0000250|UniProtKB:Q8WYN0};
GN Synonyms=APG4A {ECO:0000250|UniProtKB:Q8WYN0};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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 to reveal a C-terminal glycine. Exposure of the glycine at the
CC C-terminus is essential for ATG8 proteins conjugation to
CC phosphatidylethanolamine (PE) and insertion to membranes, which is
CC necessary for autophagy. Preferred substrate is GABARAPL2 followed by
CC MAP1LC3A and GABARAP. Protease activity is also required to counteract
CC formation of high-molecular weight conjugates of ATG8 proteins
CC (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8
CC conjugated to other proteins, such as ATG3. 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. Compared to ATG4B, the major protein for proteolytic
CC activation of ATG8 proteins, shows weaker ability to cleave the C-
CC terminal amino acid of ATG8 proteins, while it displays stronger
CC delipidation activity. 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. {ECO:0000250|UniProtKB:Q8WYN0}.
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:Q8WYN0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q8WYN0};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide. Redox-regulated
CC during autophagy since reducing conditions activate ATG4A whereas an
CC oxidizing environment such as the presence of H(2)O(2) inhibits its
CC activity. {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SUBUNIT: Interacts with ATG9A; the interaction is direct.
CC {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with the ATG8 family proteins. Required for proteolytic
CC activation and delipidation of ATG8 proteins.
CC {ECO:0000250|UniProtKB:Q8WYN0}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; CR860595; CAH92717.1; -; mRNA.
DR RefSeq; NP_001126588.1; NM_001133116.1.
DR AlphaFoldDB; Q5R699; -.
DR SMR; Q5R699; -.
DR STRING; 9601.ENSPPYP00000023081; -.
DR MEROPS; C54.002; -.
DR GeneID; 100173580; -.
DR KEGG; pon:100173580; -.
DR CTD; 115201; -.
DR eggNOG; KOG2674; Eukaryota.
DR InParanoid; Q5R699; -.
DR OrthoDB; 431748at2759; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0019786; F:Atg8-specific peptidase activity; ISS:UniProtKB.
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:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
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; IEA:UniProtKB-KW.
DR InterPro; IPR033474; ATG4A.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR PANTHER; PTHR22624:SF35; PTHR22624:SF35; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 2: Evidence at transcript level;
KW Autophagy; Cytoplasm; Hydrolase; Lipid metabolism; Protease;
KW Protein transport; Reference proteome; Thiol protease; Transport;
KW Ubl conjugation pathway.
FT CHAIN 1..398
FT /note="Cysteine protease ATG4A"
FT /id="PRO_0000215840"
FT MOTIF 393..396
FT /note="LIR"
FT /evidence="ECO:0000250|UniProtKB:Q8WYN0"
FT ACT_SITE 77
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 279
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 281
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
SQ SEQUENCE 398 AA; 45260 MW; BD5D4332584AF9F2 CRC64;
MESVLSKYEN QITIFTDYLE EYPDTDELVW ILGKQHLLKT EKSKLLSDIS ARLWFTYRRK
FSPIGGTGPS SDAGWGCMLR CGQMMLAQAL ICRHLGRDWS WEKQKEQPKE YQRILQCFLD
RKDCCYSIHQ MAQMGVGEGK SIGEWFGPNT VAQVLKKLAL FDEWNSLAVY VSMDNTVVIE
DIKKMCRVLP LGADTAGDRP PDSLTASNLS KGTSAYCSAW KPLLLIVPLR LGINQINPVY
VDAFKECFKM PQSLGALGGK PNNAYYFIGF LGDELIFLDP HTTQTFVDTG ENGTVNDQTF
HCLQSPQRMN ILNLDPSVAL GFFCKEEKDF DNWCSLVQKE ILKENLRMFE LVQKHPSHWP
PFVPPAKPEV TTTGAEFIDS TEQLEEFDLE EDFEILSV
