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Q86TL0

- ATG4D_HUMAN

UniProt

Q86TL0 - ATG4D_HUMAN

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Protein

Cysteine protease ATG4D

Gene
ATG4D, APG4D, AUTL4
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

Cysteine protease ATG4D: Cysteine protease required for the cytoplasm to vacuole transport (Cvt) and autophagy. Cleaves the C-terminal amino acid of ATG8 family proteins MAP1LC3 and GABARAPL2, 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. Has also an activity of delipidating enzyme for the PE-conjugated forms.3 Publications
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.3 Publications

Enzyme regulationi

Inhibited by N-ethylmaleimide.

Kineticsi

  1. KM=13.1 µM for MAP1LC3B1 Publication
  2. KM=7.2 µM for GABARAPL2

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei63 – 642Cleavage; by CASP3
Active sitei144 – 1441Nucleophile By similarity
Active sitei356 – 3561 Reviewed prediction
Active sitei358 – 3581 By similarity

GO - Molecular functioni

  1. cysteine-type endopeptidase activity Source: UniProtKB

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. autophagic vacuole assembly Source: RefGenome
  3. cellular response to nitrogen starvation Source: RefGenome
  4. C-terminal protein lipidation Source: RefGenome
  5. late nucleophagy Source: RefGenome
  6. mitochondrion degradation Source: RefGenome
  7. piecemeal microautophagy of nucleus Source: RefGenome
  8. protein delipidation Source: RefGenome
  9. protein processing Source: RefGenome
  10. protein targeting to membrane Source: RefGenome
  11. proteolysis Source: RefGenome
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Apoptosis, Autophagy, Protein transport, Transport, Ubl conjugation pathway

Protein family/group databases

MEROPSiC54.005.

Names & Taxonomyi

Protein namesi
Recommended name:
Cysteine protease ATG4D (EC:3.4.22.-)
Alternative name(s):
AUT-like 4 cysteine endopeptidase
Autophagin-4
Autophagy-related cysteine endopeptidase 4
Autophagy-related protein 4 homolog D
Cleaved into the following chain:
Gene namesi
Name:ATG4D
Synonyms:APG4D, AUTL4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 19

Organism-specific databases

HGNCiHGNC:20789. ATG4D.

Subcellular locationi

Chain Cysteine protease ATG4D : Cytoplasm 2 Publications
Chain Cysteine protease ATG4D, mitochondrial : Cytoplasm. Mitochondrion matrix
Note: Imported into mitochondrial matrix after cleavage by CASP3 during oxidative stress and cell death.2 Publications

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. cytosol Source: RefGenome
  3. mitochondrial matrix Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi63 – 631D → A: Abolishes cleavage by CASP3. 1 Publication

Organism-specific databases

PharmGKBiPA134907475.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 474474Cysteine protease ATG4DPRO_0000215853Add
BLAST
Chaini64 – 474411Cysteine protease ATG4D, mitochondrialPRO_0000423408Add
BLAST

Post-translational modificationi

Cleaved by CASP3 during apoptosis which leads to increased activity. The cleavage by CASP3 reveals a cryptic mitochondrial targeting sequence immediately downstream of their canonical caspase cleavage sites which leads to mitochondroal import of the protein.

Proteomic databases

PaxDbiQ86TL0.
PRIDEiQ86TL0.

PTM databases

PhosphoSiteiQ86TL0.

Expressioni

Tissue specificityi

Mainly expressed in skeletal muscle and, to a lower extent, in testis.1 Publication

Gene expression databases

ArrayExpressiQ86TL0.
BgeeiQ86TL0.
CleanExiHS_ATG4D.
GenevestigatoriQ86TL0.

Interactioni

Protein-protein interaction databases

BioGridi124401. 1 interaction.
STRINGi9606.ENSP00000311318.

Structurei

3D structure databases

ProteinModelPortaliQ86TL0.
SMRiQ86TL0. Positions 115-434.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni64 – 10340Cryptic mitochondrial signal peptideAdd
BLAST

Domaini

Residues 64 to 103 constitute a cryptic mitochondrial transit peptide which is revealed after cleavage by caspase of residues 1 to 63 upon oxidative stress and cell death. It acts then as a functional transit peptide, and allows the import of the cleaved protein into the mitochondria (1 Publication).1 Publication

Sequence similaritiesi

Belongs to the peptidase C54 family.

Phylogenomic databases

eggNOGiNOG239662.
HOGENOMiHOG000294192.
HOVERGENiHBG050537.
InParanoidiQ86TL0.
KOiK08342.
OMAiKYGWAVK.
PhylomeDBiQ86TL0.
TreeFamiTF314847.

Family and domain databases

InterProiIPR005078. Peptidase_C54.
[Graphical view]
PANTHERiPTHR22624. PTHR22624. 1 hit.
PfamiPF03416. Peptidase_C54. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q86TL0-1 [UniParc]FASTAAdd to Basket

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MNSVSPAAAQ YRSSSPEDAR RRPEARRPRG PRGPDPNGLG PSGASGPALG    50
SPGAGPSEPD EVDKFKAKFL TAWNNVKYGW VVKSRTSFSK ISSIHLCGRR 100
YRFEGEGDIQ RFQRDFVSRL WLTYRRDFPP LPGGCLTSDC GWGCMLRSGQ 150
MMLAQGLLLH FLPRDWTWAE GMGLGPPELS GSASPSRYHG PARWMPPRWA 200
QGAPELEQER RHRQIVSWFA DHPRAPFGLH RLVELGQSSG KKAGDWYGPS 250
LVAHILRKAV ESCSDVTRLV VYVSQDCTVY KADVARLVAR PDPTAEWKSV 300
VILVPVRLGG ETLNPVYVPC VKELLRCELC LGIMGGKPRH SLYFIGYQDD 350
FLLYLDPHYC QPTVDVSQAD FPLESFHCTS PRKMAFAKMD PSCTVGFYAG 400
DRKEFETLCS ELTRVLSSSS ATERYPMFTL AEGHAQDHSL DDLCSQLAQP 450
TLRLPRTGRL LRAKRPSSED FVFL 474
Length:474
Mass (Da):52,922
Last modified:June 1, 2003 - v1
Checksum:iDBD91A3F1F80D2B8
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AJ312332 mRNA. Translation: CAC85951.1.
BC068992 mRNA. Translation: AAH68992.1.
CCDSiCCDS12241.1.
RefSeqiNP_001268433.1. NM_001281504.1.
NP_116274.3. NM_032885.5.
UniGeneiHs.512799.

Genome annotation databases

EnsembliENST00000309469; ENSP00000311318; ENSG00000130734.
GeneIDi84971.
KEGGihsa:84971.
UCSCiuc002mov.3. human.

Polymorphism databases

DMDMi61211809.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AJ312332 mRNA. Translation: CAC85951.1 .
BC068992 mRNA. Translation: AAH68992.1 .
CCDSi CCDS12241.1.
RefSeqi NP_001268433.1. NM_001281504.1.
NP_116274.3. NM_032885.5.
UniGenei Hs.512799.

3D structure databases

ProteinModelPortali Q86TL0.
SMRi Q86TL0. Positions 115-434.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 124401. 1 interaction.
STRINGi 9606.ENSP00000311318.

Protein family/group databases

MEROPSi C54.005.

PTM databases

PhosphoSitei Q86TL0.

Polymorphism databases

DMDMi 61211809.

Proteomic databases

PaxDbi Q86TL0.
PRIDEi Q86TL0.

Protocols and materials databases

DNASUi 84971.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000309469 ; ENSP00000311318 ; ENSG00000130734 .
GeneIDi 84971.
KEGGi hsa:84971.
UCSCi uc002mov.3. human.

Organism-specific databases

CTDi 84971.
GeneCardsi GC19P010654.
HGNCi HGNC:20789. ATG4D.
MIMi 611340. gene.
neXtProti NX_Q86TL0.
PharmGKBi PA134907475.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG239662.
HOGENOMi HOG000294192.
HOVERGENi HBG050537.
InParanoidi Q86TL0.
KOi K08342.
OMAi KYGWAVK.
PhylomeDBi Q86TL0.
TreeFami TF314847.

Miscellaneous databases

GenomeRNAii 84971.
NextBioi 75518.
PROi Q86TL0.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q86TL0.
Bgeei Q86TL0.
CleanExi HS_ATG4D.
Genevestigatori Q86TL0.

Family and domain databases

InterProi IPR005078. Peptidase_C54.
[Graphical view ]
PANTHERi PTHR22624. PTHR22624. 1 hit.
Pfami PF03416. Peptidase_C54. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy."
    Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.
    J. Biol. Chem. 278:3671-3678(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
    Tissue: Fetal liver.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Ovary.
  3. "Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis."
    Betin V.M., Lane J.D.
    J. Cell Sci. 122:2554-2566(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CLEAVAGE BY CASP3, MUTAGENESIS OF ASP-63, SUBCELLULAR LOCATION.
  4. "Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates."
    Li M., Hou Y., Wang J., Chen X., Shao Z.M., Yin X.M.
    J. Biol. Chem. 286:7327-7338(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
  5. "A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress."
    Betin V.M., MacVicar T.D., Parsons S.F., Anstee D.J., Lane J.D.
    Autophagy 8:664-676(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION (CYSTEINE PROTEASE ATG4D, MITOCHONDRIAL), CLEAVAGE BY CASP3, SUBCELLULAR LOCATION, DOMAIN, CRYPTIC SIGNAL PEPTIDE.

Entry informationi

Entry nameiATG4D_HUMAN
AccessioniPrimary (citable) accession number: Q86TL0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: June 1, 2003
Last modified: September 3, 2014
This is version 93 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Peptidase families
    Classification of peptidase families and list of entries
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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