Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Cysteine protease ATG4D

Gene

ATG4D

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

    • cysteine-type endopeptidase activity Source: UniProtKB

    GO - Biological processi

    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 Componenti: Chromosome 19

    Organism-specific databases

    HGNCiHGNC:20789. ATG4D.

    Subcellular locationi

    Cysteine protease ATG4D, mitochondrial :

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • cytosol Source: GO_Central
    • 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.

    Polymorphism and mutation databases

    BioMutaiATG4D.
    DMDMi61211809.

    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.
    GenevisibleiQ86TL0. HS.

    Interactioni

    Protein-protein interaction databases

    BioGridi124401. 7 interactions.
    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. AlignAdd to basket

    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]
    uc010dxj.3. human.

    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.
    CCDSiCCDS12241.1. [Q86TL0-1]
    RefSeqiNP_001268433.1. NM_001281504.1.
    NP_116274.3. NM_032885.5. [Q86TL0-1]
    UniGeneiHs.512799.

    3D structure databases

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

    Protein-protein interaction databases

    BioGridi124401. 7 interactions.
    STRINGi9606.ENSP00000311318.

    Protein family/group databases

    MEROPSiC54.005.

    PTM databases

    PhosphoSiteiQ86TL0.

    Polymorphism and mutation databases

    BioMutaiATG4D.
    DMDMi61211809.

    Proteomic databases

    MaxQBiQ86TL0.
    PaxDbiQ86TL0.
    PRIDEiQ86TL0.

    Protocols and materials databases

    DNASUi84971.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000309469; ENSP00000311318; ENSG00000130734. [Q86TL0-1]
    GeneIDi84971.
    KEGGihsa:84971.
    UCSCiuc002mov.3. human. [Q86TL0-1]
    uc010dxj.3. human.

    Organism-specific databases

    CTDi84971.
    GeneCardsiGC19P010654.
    HGNCiHGNC:20789. ATG4D.
    MIMi611340. gene.
    neXtProtiNX_Q86TL0.
    PharmGKBiPA134907475.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiNOG239662.
    GeneTreeiENSGT00530000063000.
    HOGENOMiHOG000294192.
    HOVERGENiHBG050537.
    InParanoidiQ86TL0.
    KOiK08342.
    OMAiKYGWAVK.
    PhylomeDBiQ86TL0.
    TreeFamiTF314847.

    Miscellaneous databases

    ChiTaRSiATG4D. human.
    GenomeRNAii84971.
    NextBioi75518.
    PROiQ86TL0.
    SOURCEiSearch...

    Gene expression databases

    BgeeiQ86TL0.
    CleanExiHS_ATG4D.
    ExpressionAtlasiQ86TL0. baseline.
    GenevisibleiQ86TL0. HS.

    Family and domain databases

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

    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: June 24, 2015
    This is version 102 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

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.