| IED ID | IndEnz0002014413 |
| Enzyme Type ID | protease014413 |
| Protein Name |
Cysteine protease ATG4D EC 3.4.22.- AUT-like 4 cysteine endopeptidase Autophagy-related cysteine endopeptidase 4 Autophagin-4 Autophagy-related protein 4 homolog D HsAPG4D Cleaved into: Cysteine protease ATG4D, mitochondrial |
| Gene Name | ATG4D APG4D AUTL4 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MNSVSPAAAQYRSSSPEDARRRPEARRPRGPRGPDPNGLGPSGASGPALGSPGAGPSEPDEVDKFKAKFLTAWNNVKYGWVVKSRTSFSKISSIHLCGRRYRFEGEGDIQRFQRDFVSRLWLTYRRDFPPLPGGCLTSDCGWGCMLRSGQMMLAQGLLLHFLPRDWTWAEGMGLGPPELSGSASPSRYHGPARWMPPRWAQGAPELEQERRHRQIVSWFADHPRAPFGLHRLVELGQSSGKKAGDWYGPSLVAHILRKAVESCSDVTRLVVYVSQDCTVYKADVARLVARPDPTAEWKSVVILVPVRLGGETLNPVYVPCVKELLRCELCLGIMGGKPRHSLYFIGYQDDFLLYLDPHYCQPTVDVSQADFPLESFHCTSPRKMAFAKMDPSCTVGFYAGDRKEFETLCSELTRVLSSSSATERYPMFTLAEGHAQDHSLDDLCSQLAQPTLRLPRTGRLLRAKRPSSEDFVFL |
| Enzyme Length | 474 |
| Uniprot Accession Number | Q86TL0 |
| Absorption | |
| Active Site | ACT_SITE 144; /note=Nucleophile; /evidence=ECO:0000250|UniProtKB:Q9Y4P1; ACT_SITE 356; /evidence=ECO:0000250|UniProtKB:Q9Y4P1; ACT_SITE 358; /evidence=ECO:0000250|UniProtKB:Q9Y4P1 |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by N-ethylmaleimide. {ECO:0000269|PubMed:21177865}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine; Xref=Rhea:RHEA:67548, Rhea:RHEA-COMP:17323, Rhea:RHEA-COMP:17324, ChEBI:CHEBI:15377, ChEBI:CHEBI:64612, ChEBI:CHEBI:172940, ChEBI:CHEBI:172941; Evidence={ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:33909989};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549; Evidence={ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:33909989}; CATALYTIC ACTIVITY: Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylserine + H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-glycero-3-phospho-L-serine; Xref=Rhea:RHEA:67576, Rhea:RHEA-COMP:17324, Rhea:RHEA-COMP:17326, ChEBI:CHEBI:15377, ChEBI:CHEBI:57262, ChEBI:CHEBI:172940, ChEBI:CHEBI:172942; Evidence={ECO:0000269|PubMed:33909989};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67577; Evidence={ECO:0000269|PubMed:33909989}; |
| DNA Binding | |
| EC Number | 3.4.22.- |
| Enzyme Function | FUNCTION: [Cysteine protease ATG4D]: Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins (PubMed:21177865, PubMed:29458288, PubMed:30661429). The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3 and GABARAPL2, to reveal a C-terminal glycine (PubMed:21177865). 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 (By similarity). In addition to the protease activity, also mediates delipidation of ATG8 family proteins (PubMed:29458288, PubMed:33909989). Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy (PubMed:29458288, PubMed:33909989). Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, by catalyzing delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) (PubMed:33909989). ATG4D plays a role in the autophagy-mediated neuronal homeostasis in the central nervous system (By similarity). Compared to other members of the family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the delipidation activity, while it promotes weak proteolytic activation of ATG8 proteins (By similarity). 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 (PubMed:33773106). {ECO:0000250|UniProtKB:Q8BGV9, ECO:0000250|UniProtKB:Q9Y4P1, ECO:0000269|PubMed:21177865, ECO:0000269|PubMed:29458288, ECO:0000269|PubMed:30661429, ECO:0000269|PubMed:33773106, ECO:0000269|PubMed:33909989}.; FUNCTION: [Cysteine protease ATG4D, mitochondrial]: Plays a role as an autophagy regulator that links mitochondrial dysfunction with apoptosis. The mitochondrial import of ATG4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability. {ECO:0000269|PubMed:19549685, ECO:0000269|PubMed:22441018}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Alternative sequence (1); Chain (2); Compositional bias (1); Modified residue (1); Mutagenesis (1); Natural variant (4); Region (2); Site (1) |
| Keywords | Alternative splicing;Apoptosis;Autophagy;Cytoplasm;Hydrolase;Mitochondrion;Phosphoprotein;Protease;Protein transport;Reference proteome;Thiol protease;Transport;Ubl conjugation pathway |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Cysteine protease ATG4D]: Cytoplasm {ECO:0000269|PubMed:19549685}.; SUBCELLULAR LOCATION: [Cysteine protease ATG4D, mitochondrial]: Cytoplasm {ECO:0000269|PubMed:19549685}. Mitochondrion matrix {ECO:0000269|PubMed:19549685, ECO:0000269|PubMed:22441018}. Note=Imported into mitochondrial matrix after cleavage by CASP3 during oxidative stress and cell death. {ECO:0000269|PubMed:22441018}. |
| Modified Residue | MOD_RES 467; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:23186163 |
| Post Translational Modification | PTM: Cleaved by CASP3 during apoptosis which leads to increased activity (PubMed:19549685, PubMed:22441018). The cleavage by CASP3 reveals a cryptic mitochondrial targeting sequence immediately downstream of their canonical caspase cleavage sites which leads to mitochondrial import of the protein (PubMed:19549685, PubMed:22441018). {ECO:0000269|PubMed:19549685, ECO:0000269|PubMed:22441018}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 15187094; 19322194; 23508006; 27265029; 28834690; 30374741; |
| Motif | |
| Gene Encoded By | |
| Mass | 52,922 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=13.1 uM for MAP1LC3B {ECO:0000269|PubMed:21177865}; KM=7.2 uM for GABARAPL2 {ECO:0000269|PubMed:21177865}; |
| Metal Binding | |
| Rhea ID | RHEA:67548; RHEA:67549; RHEA:67576; RHEA:67577 |
| Cross Reference Brenda |