Q86TL0 · ATG4D_HUMAN
- ProteinCysteine protease ATG4D
- GeneATG4D
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids474 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Cysteine protease ATG4D
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).
Cysteine protease ATG4D, mitochondrial
Catalytic activity
- [protein]-C-terminal L-amino acid-glycyl-phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamineThis reaction proceeds in the forward direction.
- [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-serineThis reaction proceeds in the forward direction.
Activity regulation
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
13.1 μM | MAP1LC3B | |||||
7.2 μM | GABARAPL2 |
Features
Showing features for site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 63-64 | Cleavage; by CASP3 | ||||
Sequence: DK | ||||||
Active site | 144 | Nucleophile | ||||
Sequence: C | ||||||
Active site | 356 | |||||
Sequence: D | ||||||
Active site | 358 | |||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | mitochondrial matrix | |
Cellular Component | mitochondrion | |
Cellular Component | nucleoplasm | |
Molecular Function | cysteine-type endopeptidase activity | |
Molecular Function | cysteine-type exopeptidase activity | |
Molecular Function | cysteine-type peptidase activity | |
Molecular Function | protein-phosphatidylethanolamide deconjugating activity | |
Biological Process | aggrephagy | |
Biological Process | apoptotic process | |
Biological Process | autophagosome assembly | |
Biological Process | autophagy | |
Biological Process | mitophagy | |
Biological Process | piecemeal microautophagy of the nucleus | |
Biological Process | protein delipidation | |
Biological Process | protein localization to phagophore assembly site | |
Biological Process | protein processing | |
Biological Process | protein transport | |
Biological Process | proteolysis |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameCysteine protease ATG4D
- EC number
- Alternative names
- Cleaved into 1 chains
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ86TL0
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Cysteine protease ATG4D
Cysteine protease ATG4D, mitochondrial
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 63 | Abolishes cleavage by CASP3. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_085353 | 125 | found in patients with non-obstructive azoospermia; uncertain significance; decreased expression of MAP1LC3B; increased programmed cell death in spermatogenic cells; dbSNP:rs1216040637 | |||
Sequence: R → L | ||||||
Natural variant | VAR_085354 | 273 | found in patients with non-obstructive azoospermia; uncertain significance; dbSNP:rs145807760 | |||
Sequence: V → I | ||||||
Natural variant | VAR_085355 | 295 | found in patients with non-obstructive azoospermia; uncertain significance; dbSNP:rs1261979779 | |||
Sequence: A → D | ||||||
Natural variant | VAR_085356 | 395 | found in patients with non-obstructive azoospermia; uncertain significance; dbSNP:rs201291151 | |||
Sequence: V → M |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 572 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000215853 | 1-474 | UniProt | Cysteine protease ATG4D | |||
Sequence: MNSVSPAAAQYRSSSPEDARRRPEARRPRGPRGPDPNGLGPSGASGPALGSPGAGPSEPDEVDKFKAKFLTAWNNVKYGWVVKSRTSFSKISSIHLCGRRYRFEGEGDIQRFQRDFVSRLWLTYRRDFPPLPGGCLTSDCGWGCMLRSGQMMLAQGLLLHFLPRDWTWAEGMGLGPPELSGSASPSRYHGPARWMPPRWAQGAPELEQERRHRQIVSWFADHPRAPFGLHRLVELGQSSGKKAGDWYGPSLVAHILRKAVESCSDVTRLVVYVSQDCTVYKADVARLVARPDPTAEWKSVVILVPVRLGGETLNPVYVPCVKELLRCELCLGIMGGKPRHSLYFIGYQDDFLLYLDPHYCQPTVDVSQADFPLESFHCTSPRKMAFAKMDPSCTVGFYAGDRKEFETLCSELTRVLSSSSATERYPMFTLAEGHAQDHSLDDLCSQLAQPTLRLPRTGRLLRAKRPSSEDFVFL | |||||||
Chain | PRO_0000423408 | 64-474 | UniProt | Cysteine protease ATG4D, mitochondrial | |||
Sequence: KFKAKFLTAWNNVKYGWVVKSRTSFSKISSIHLCGRRYRFEGEGDIQRFQRDFVSRLWLTYRRDFPPLPGGCLTSDCGWGCMLRSGQMMLAQGLLLHFLPRDWTWAEGMGLGPPELSGSASPSRYHGPARWMPPRWAQGAPELEQERRHRQIVSWFADHPRAPFGLHRLVELGQSSGKKAGDWYGPSLVAHILRKAVESCSDVTRLVVYVSQDCTVYKADVARLVARPDPTAEWKSVVILVPVRLGGETLNPVYVPCVKELLRCELCLGIMGGKPRHSLYFIGYQDDFLLYLDPHYCQPTVDVSQADFPLESFHCTSPRKMAFAKMDPSCTVGFYAGDRKEFETLCSELTRVLSSSSATERYPMFTLAEGHAQDHSLDDLCSQLAQPTLRLPRTGRLLRAKRPSSEDFVFL | |||||||
Modified residue | 467 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 467 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 468 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
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).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-60 | Disordered | ||||
Sequence: MNSVSPAAAQYRSSSPEDARRRPEARRPRGPRGPDPNGLGPSGASGPALGSPGAGPSEPD | ||||||
Compositional bias | 15-31 | Basic and acidic residues | ||||
Sequence: SPEDARRRPEARRPRGP | ||||||
Region | 64-103 | Cryptic mitochondrial signal peptide | ||||
Sequence: KFKAKFLTAWNNVKYGWVVKSRTSFSKISSIHLCGRRYRF |
Domain
It acts then as a functional transit peptide, and allows the import of the cleaved protein into the mitochondria (PubMed:22441018).
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q86TL0-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length474
- Mass (Da)52,922
- Last updated2003-06-01 v1
- ChecksumDBD91A3F1F80D2B8
Q86TL0-2
- Name2
- Differences from canonical
- 1-333: Missing
Computationally mapped potential isoform sequences
There are 10 potential isoforms mapped to this entry
Features
Showing features for alternative sequence, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_056671 | 1-333 | in isoform 2 | |||
Sequence: Missing | ||||||
Compositional bias | 15-31 | Basic and acidic residues | ||||
Sequence: SPEDARRRPEARRPRGP |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AJ312332 EMBL· GenBank· DDBJ | CAC85951.1 EMBL· GenBank· DDBJ | mRNA | ||
AC011461 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471106 EMBL· GenBank· DDBJ | EAW84116.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC007639 EMBL· GenBank· DDBJ | AAH07639.1 EMBL· GenBank· DDBJ | mRNA | ||
BC016845 EMBL· GenBank· DDBJ | AAH16845.1 EMBL· GenBank· DDBJ | mRNA | ||
BC068992 EMBL· GenBank· DDBJ | AAH68992.1 EMBL· GenBank· DDBJ | mRNA |