Protein: Cysteine protease ATG4A (EC 3.4.22.-) (AUT-like 2 cysteine endopeptidase) (Autophagy-related cysteine endopeptidase 2) (Autophagin-2) (Autophagy-related protein 4 homolog A) (HsAPG4A) (hAPG4A) (Q8WYN0)
Organism: Homo sapiens (Human)
Function: Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP. Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity. Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy.
Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:Q8BGE6}.
Sequence: MESVLSKYEDQITIFTDYLEEYPDTDELVWILGKQHLLKTEKSKLLSDISARLWFTYRRKFSPIGGTGPSSDAGWGCMLRCGQMMLAQALICRHLGRDWSWEKQKEQPKEYQRILQCFLDRKDCCYSIHQMAQMGVGEGKSIGEWFGPNTVAQVLKKLALFDEWNSLAVYVSMDNTVVIEDIKKMCRVLPLSADTAGDRPPDSLTASNQSKGTSAYCSAWKPLLLIVPLRLGINQINPVYVDAFKECFKMPQSLGALGGKPNNAYYFIGFLGDELIFLDPHTTQTFVDTEENGTVNDQTFHCLQSPQRMNILNLDPSVALGFFCKEEKDFDNWCSLVQKEILKENLRMFELVQKHPSHWPPFVPPAKPEVTTTGAEFIDSTEQLEEFDLEEDFEILSV
InterPro domains: - IPR005078: Peptidase C54 (family) [18-372]
- IPR046793: Cysteine protease ATG4, F-type LIR motif (conserved_site) [369-396]
- IPR038765: Papain-like cysteine peptidase superfamily (homologous_superfamily) [26-359]
- IPR046792: Peptidase C54, catalytic domain (domain) [43-335]
Interaction partners: - Gamma-aminobutyric acid receptor-associated protein
- GABA type A receptor associated protein like 1
- Gamma-aminobutyric acid receptor-associated protein-like 2
- Serine/threonine-protein kinase ULK1
- Serine/threonine-protein kinase ULK2
- Microtubule-associated protein 1 light chain 3 beta
- Ubiquitin-like-conjugating enzyme ATG3
- Ubiquitin-like modifier-activating enzyme ATG7
- Ubiquitin-like protein ATG12
- Microtubule-associated protein 1 light chain 3 alpha
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016787 (hydrolase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0008233 (peptidase activity), GO:0097110 (scaffold protein binding), GO:0008234 (cysteine-type peptidase activity), GO:0004175 (endopeptidase activity), GO:0019783 (ubiquitin-like protein peptidase activity), GO:0004197 (cysteine-type endopeptidase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0051179 (localization), GO:0009987 (cellular process), GO:0051641 (cellular localization), GO:0044237 (cellular metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0061919 (process utilizing autophagic mechanism), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0044238 (primary metabolic process), GO:0033036 (macromolecule localization), GO:0044085 (cellular component biogenesis), GO:1901564 (organonitrogen compound metabolic process), GO:0006914 (autophagy), GO:0044248 (cellular catabolic process), GO:0019538 (protein metabolic process), GO:0070727 (cellular macromolecule localization), GO:0016043 (cellular component organization), GO:0043170 (macromolecule metabolic process), GO:0036211 (protein modification process), GO:0016236 (macroautophagy), GO:0043412 (macromolecule modification), GO:0006508 (proteolysis), GO:0000422 (autophagy of mitochondrion), GO:0016237 (lysosomal microautophagy), GO:0008104 (protein localization), GO:0006996 (organelle organization), GO:0022411 (cellular component disassembly), GO:0022607 (cellular component assembly), GO:0070925 (organelle assembly), GO:0007005 (mitochondrion organization), GO:0061912 (selective autophagy), GO:0007033 (vacuole organization), GO:0000423 (mitophagy), GO:0034497 (protein localization to phagophore assembly site), GO:1905037 (autophagosome organization), GO:1903008 (organelle disassembly), GO:0000045 (autophagosome assembly), GO:0061726 (mitochondrion disassembly)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005737 (cytoplasm), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure)