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Q86TL0

- ATG4D_HUMAN

UniProt

Q86TL0 - ATG4D_HUMAN

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Protein

Cysteine protease ATG4D

Gene

ATG4D

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.
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.

Enzyme regulationi

Inhibited by N-ethylmaleimide.

Kineticsi

  1. KM=13.1 µM for MAP1LC3B1 Publication
  2. KM=7.2 µM for GABARAPL21 Publication

Sites

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

GO - Molecular functioni

  1. cysteine-type endopeptidase activity Source: UniProtKB

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. autophagy Source: UniProtKB-KW
  3. protein transport Source: UniProtKB-KW
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, mitochondrial : Cytoplasm. Mitochondrion matrix
Note: Imported into mitochondrial matrix after cleavage by CASP3 during oxidative stress and cell death.

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. mitochondrion Source: UniProtKB-KW
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.2 Publications

Proteomic databases

MaxQBiQ86TL0.
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

BgeeiQ86TL0.
CleanExiHS_ATG4D.
ExpressionAtlasiQ86TL0. baseline and differential.
GenevestigatoriQ86TL0.

Interactioni

Protein-protein interaction databases

BioGridi124401. 1 interaction.
STRINGi9606.ENSP00000311318.

Structurei

3D structure databases

ProteinModelPortaliQ86TL0.
SMRiQ86TL0. Positions 115-434.
ModBaseiSearch...
MobiDBiSearch...

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 (PubMed:22441018).1 Publication

Sequence similaritiesi

Belongs to the peptidase C54 family.Curated

Phylogenomic databases

eggNOGiNOG239662.
GeneTreeiENSGT00530000063000.
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]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q86TL0-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MNSVSPAAAQ YRSSSPEDAR RRPEARRPRG PRGPDPNGLG PSGASGPALG
60 70 80 90 100
SPGAGPSEPD EVDKFKAKFL TAWNNVKYGW VVKSRTSFSK ISSIHLCGRR
110 120 130 140 150
YRFEGEGDIQ RFQRDFVSRL WLTYRRDFPP LPGGCLTSDC GWGCMLRSGQ
160 170 180 190 200
MMLAQGLLLH FLPRDWTWAE GMGLGPPELS GSASPSRYHG PARWMPPRWA
210 220 230 240 250
QGAPELEQER RHRQIVSWFA DHPRAPFGLH RLVELGQSSG KKAGDWYGPS
260 270 280 290 300
LVAHILRKAV ESCSDVTRLV VYVSQDCTVY KADVARLVAR PDPTAEWKSV
310 320 330 340 350
VILVPVRLGG ETLNPVYVPC VKELLRCELC LGIMGGKPRH SLYFIGYQDD
360 370 380 390 400
FLLYLDPHYC QPTVDVSQAD FPLESFHCTS PRKMAFAKMD PSCTVGFYAG
410 420 430 440 450
DRKEFETLCS ELTRVLSSSS ATERYPMFTL AEGHAQDHSL DDLCSQLAQP
460 470
TLRLPRTGRL LRAKRPSSED FVFL
Length:474
Mass (Da):52,922
Last modified:June 1, 2003 - v1
Checksum:iDBD91A3F1F80D2B8
GO
Isoform 2 (identifier: Q86TL0-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-333: Missing.

Note: No experimental confirmation available.

Show »
Length:141
Mass (Da):16,008
Checksum:iC30E0A97CBB1E2D2
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 333333Missing in isoform 2. 1 PublicationVSP_056671Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ312332 mRNA. Translation: CAC85951.1.
AC011461 Genomic DNA. No translation available.
CH471106 Genomic DNA. Translation: EAW84116.1.
BC007639 mRNA. Translation: AAH07639.1.
BC016845 mRNA. Translation: AAH16845.1.
BC068992 mRNA. Translation: AAH68992.1.
CCDSiCCDS12241.1. [Q86TL0-1]
RefSeqiNP_001268433.1. NM_001281504.1.
NP_116274.3. NM_032885.5. [Q86TL0-1]
UniGeneiHs.512799.

Genome annotation databases

EnsembliENST00000309469; ENSP00000311318; ENSG00000130734. [Q86TL0-1]
GeneIDi84971.
KEGGihsa:84971.
UCSCiuc002mov.3. human. [Q86TL0-1]

Polymorphism databases

DMDMi61211809.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ312332 mRNA. Translation: CAC85951.1 .
AC011461 Genomic DNA. No translation available.
CH471106 Genomic DNA. Translation: EAW84116.1 .
BC007639 mRNA. Translation: AAH07639.1 .
BC016845 mRNA. Translation: AAH16845.1 .
BC068992 mRNA. Translation: AAH68992.1 .
CCDSi CCDS12241.1. [Q86TL0-1 ]
RefSeqi NP_001268433.1. NM_001281504.1.
NP_116274.3. NM_032885.5. [Q86TL0-1 ]
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

MaxQBi Q86TL0.
PaxDbi Q86TL0.
PRIDEi Q86TL0.

Protocols and materials databases

DNASUi 84971.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000309469 ; ENSP00000311318 ; ENSG00000130734 . [Q86TL0-1 ]
GeneIDi 84971.
KEGGi hsa:84971.
UCSCi uc002mov.3. human. [Q86TL0-1 ]

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.
GeneTreei ENSGT00530000063000.
HOGENOMi HOG000294192.
HOVERGENi HBG050537.
InParanoidi Q86TL0.
KOi K08342.
OMAi KYGWAVK.
PhylomeDBi Q86TL0.
TreeFami TF314847.

Miscellaneous databases

ChiTaRSi ATG4D. human.
GenomeRNAii 84971.
NextBioi 75518.
PROi Q86TL0.
SOURCEi Search...

Gene expression databases

Bgeei Q86TL0.
CleanExi HS_ATG4D.
ExpressionAtlasi Q86TL0. baseline and differential.
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] (ISOFORM 1), TISSUE SPECIFICITY.
    Tissue: Fetal liver.
  2. "The DNA sequence and biology of human chromosome 19."
    Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V.
    , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
    Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "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] (ISOFORMS 1 AND 2).
    Tissue: Lung, Ovary and Uterus.
  5. "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.
  6. "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.
  7. "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
Secondary accession number(s): Q969K0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: June 1, 2003
Last modified: November 26, 2014
This is version 96 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