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Q86TL0 (ATG4D_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 89. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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:

  1. Cysteine protease ATG4D, mitochondrial
Gene names
Name:ATG4D
Synonyms:APG4D, AUTL4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length474 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3 Ref.4 Ref.5

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. Ref.3 Ref.4 Ref.5

Enzyme regulation

Inhibited by N-ethylmaleimide.

Subcellular location

Cysteine protease ATG4D: Cytoplasm.

Cysteine protease ATG4D, mitochondrial: Cytoplasm. Mitochondrion matrix. Note: Imported into mitochondrial matrix after cleavage by CASP3 during oxidative stress and cell death. Ref.3 Ref.5

Tissue specificity

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

Domain

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 (Ref.5). Ref.5

Post-translational modification

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.

Sequence similarities

Belongs to the peptidase C54 family.

Biophysicochemical properties

Kinetic parameters:

KM=13.1 µM for MAP1LC3B Ref.4

KM=7.2 µM for GABARAPL2

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 474474Cysteine protease ATG4D
PRO_0000215853
Chain64 – 474411Cysteine protease ATG4D, mitochondrial
PRO_0000423408

Regions

Region64 – 10340Cryptic mitochondrial signal peptide

Sites

Active site1441Nucleophile By similarity
Active site3561 Potential
Active site3581 By similarity
Site63 – 642Cleavage; by CASP3

Experimental info

Mutagenesis631D → A: Abolishes cleavage by CASP3. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q86TL0 [UniParc].

Last modified June 1, 2003. Version 1.
Checksum: DBD91A3F1F80D2B8

FASTA47452,922
        10         20         30         40         50         60 
MNSVSPAAAQ YRSSSPEDAR RRPEARRPRG PRGPDPNGLG PSGASGPALG SPGAGPSEPD 

        70         80         90        100        110        120 
EVDKFKAKFL TAWNNVKYGW VVKSRTSFSK ISSIHLCGRR YRFEGEGDIQ RFQRDFVSRL 

       130        140        150        160        170        180 
WLTYRRDFPP LPGGCLTSDC GWGCMLRSGQ MMLAQGLLLH FLPRDWTWAE GMGLGPPELS 

       190        200        210        220        230        240 
GSASPSRYHG PARWMPPRWA QGAPELEQER RHRQIVSWFA DHPRAPFGLH RLVELGQSSG 

       250        260        270        280        290        300 
KKAGDWYGPS LVAHILRKAV ESCSDVTRLV VYVSQDCTVY KADVARLVAR PDPTAEWKSV 

       310        320        330        340        350        360 
VILVPVRLGG ETLNPVYVPC VKELLRCELC LGIMGGKPRH SLYFIGYQDD FLLYLDPHYC 

       370        380        390        400        410        420 
QPTVDVSQAD FPLESFHCTS PRKMAFAKMD PSCTVGFYAG DRKEFETLCS ELTRVLSSSS 

       430        440        450        460        470 
ATERYPMFTL AEGHAQDHSL DDLCSQLAQP TLRLPRTGRL LRAKRPSSED FVFL 

« Hide

References

« Hide 'large scale' references
[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AJ312332 mRNA. Translation: CAC85951.1.
BC068992 mRNA. Translation: AAH68992.1.
RefSeqNP_001268433.1. NM_001281504.1.
NP_116274.3. NM_032885.5.
UniGeneHs.512799.

3D structure databases

ProteinModelPortalQ86TL0.
SMRQ86TL0. Positions 94-434.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid124401. 1 interaction.
STRING9606.ENSP00000311318.

Protein family/group databases

MEROPSC54.005.

PTM databases

PhosphoSiteQ86TL0.

Polymorphism databases

DMDM61211809.

Proteomic databases

PaxDbQ86TL0.
PRIDEQ86TL0.

Protocols and materials databases

DNASU84971.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000309469; ENSP00000311318; ENSG00000130734.
GeneID84971.
KEGGhsa:84971.
UCSCuc002mov.3. human.

Organism-specific databases

CTD84971.
GeneCardsGC19P010654.
HGNCHGNC:20789. ATG4D.
MIM611340. gene.
neXtProtNX_Q86TL0.
PharmGKBPA134907475.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG239662.
HOGENOMHOG000294192.
HOVERGENHBG050537.
InParanoidQ86TL0.
KOK08342.
OMAKYGWAVK.
PhylomeDBQ86TL0.
TreeFamTF314847.

Gene expression databases

ArrayExpressQ86TL0.
BgeeQ86TL0.
CleanExHS_ATG4D.
GenevestigatorQ86TL0.

Family and domain databases

InterProIPR005078. Peptidase_C54.
[Graphical view]
PANTHERPTHR22624. PTHR22624. 1 hit.
PfamPF03416. Peptidase_C54. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi84971.
NextBio75518.
PROQ86TL0.
SOURCESearch...

Entry information

Entry nameATG4D_HUMAN
AccessionPrimary (citable) accession number: Q86TL0
Entry history
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: June 1, 2003
Last modified: April 16, 2014
This is version 89 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM