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Protein

Cysteine protease ATG4D

Gene

ATG4D

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

Activity 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)DescriptionActionsGraphical viewLength
    Active sitei144NucleophileBy similarity1
    Active sitei356Sequence analysis1
    Active sitei358By similarity1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase, Protease, Thiol protease
    Biological processApoptosis, Autophagy, Protein transport, Transport, Ubl conjugation pathway

    Enzyme and pathway databases

    ReactomeiR-HSA-1632852 Macroautophagy

    Protein family/group databases

    MEROPSiC54.005
    TCDBi9.A.15.2.1 the autophagy-related phagophore-formation transporter (apt) family

    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
    Proteomesi
    • UP000005640 Componenti: Chromosome 19

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000130734.9
    HGNCiHGNC:20789 ATG4D
    MIMi611340 gene
    neXtProtiNX_Q86TL0

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi63D → A: Abolishes cleavage by CASP3. 1 Publication1

    Organism-specific databases

    OpenTargetsiENSG00000130734
    PharmGKBiPA134907475

    Polymorphism and mutation databases

    BioMutaiATG4D
    DMDMi61211809

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002158531 – 474Cysteine protease ATG4DAdd BLAST474
    ChainiPRO_000042340864 – 474Cysteine protease ATG4D, mitochondrialAdd BLAST411

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei467PhosphoserineCombined sources1

    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 mitochondrial import of the protein.2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sitei63 – 64Cleavage; by CASP32

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    EPDiQ86TL0
    MaxQBiQ86TL0
    PaxDbiQ86TL0
    PeptideAtlasiQ86TL0
    PRIDEiQ86TL0
    ProteomicsDBi69710

    PTM databases

    iPTMnetiQ86TL0
    PhosphoSitePlusiQ86TL0

    Expressioni

    Tissue specificityi

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

    Gene expression databases

    BgeeiENSG00000130734 Expressed in 197 organ(s), highest expression level in testis
    CleanExiHS_ATG4D
    ExpressionAtlasiQ86TL0 baseline and differential
    GenevisibleiQ86TL0 HS

    Organism-specific databases

    HPAiHPA067683

    Interactioni

    Protein-protein interaction databases

    BioGridi124401, 9 interactors
    STRINGi9606.ENSP00000311318

    Structurei

    3D structure databases

    ProteinModelPortaliQ86TL0
    SMRiQ86TL0
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni64 – 103Cryptic mitochondrial signal peptideAdd BLAST40

    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

    eggNOGiKOG2674 Eukaryota
    ENOG410XPQ0 LUCA
    GeneTreeiENSGT00530000063000
    HOGENOMiHOG000294192
    HOVERGENiHBG050537
    InParanoidiQ86TL0
    KOiK08342
    OMAiNREHHEA
    OrthoDBiEOG091G065S
    PhylomeDBiQ86TL0
    TreeFamiTF314847

    Family and domain databases

    InterProiView protein in InterPro
    IPR038765 Papain_like_cys_pep_sf
    IPR005078 Peptidase_C54
    PANTHERiPTHR22624 PTHR22624, 1 hit
    PfamiView protein in Pfam
    PF03416 Peptidase_C54, 1 hit
    SUPFAMiSSF54001 SSF54001, 1 hit

    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

    This entry has 2 described isoforms and 10 potential isoforms that are computationally mapped.Show allAlign All

    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

    Computationally mapped potential isoform sequencesi

    There are 10 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    K7EPJ0K7EPJ0_HUMAN
    Cysteine protease
    ATG4D hCG_28499
    228Annotation score:
    K7EJA5K7EJA5_HUMAN
    Cysteine protease
    ATG4D
    177Annotation score:
    K7ERK1K7ERK1_HUMAN
    Cysteine protease
    ATG4D
    334Annotation score:
    K7EN30K7EN30_HUMAN
    Cysteine protease
    ATG4D
    177Annotation score:
    K7EQ67K7EQ67_HUMAN
    Cysteine protease
    ATG4D
    99Annotation score:
    K7ESM7K7ESM7_HUMAN
    Cysteine protease
    ATG4D
    203Annotation score:
    K7EP43K7EP43_HUMAN
    Cysteine protease
    ATG4D
    209Annotation score:
    K7EMB9K7EMB9_HUMAN
    Cysteine protease
    ATG4D
    67Annotation score:
    K7EKP6K7EKP6_HUMAN
    Cysteine protease ATG4D
    ATG4D
    120Annotation score:
    K7EQN3K7EQN3_HUMAN
    Cysteine protease ATG4D
    ATG4D
    160Annotation score:

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0566711 – 333Missing in isoform 2. 1 PublicationAdd BLAST333

    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.5 human [Q86TL0-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    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
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi124401, 9 interactors
    STRINGi9606.ENSP00000311318

    Protein family/group databases

    MEROPSiC54.005
    TCDBi9.A.15.2.1 the autophagy-related phagophore-formation transporter (apt) family

    PTM databases

    iPTMnetiQ86TL0
    PhosphoSitePlusiQ86TL0

    Polymorphism and mutation databases

    BioMutaiATG4D
    DMDMi61211809

    Proteomic databases

    EPDiQ86TL0
    MaxQBiQ86TL0
    PaxDbiQ86TL0
    PeptideAtlasiQ86TL0
    PRIDEiQ86TL0
    ProteomicsDBi69710

    Protocols and materials databases

    DNASUi84971
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000309469; ENSP00000311318; ENSG00000130734 [Q86TL0-1]
    GeneIDi84971
    KEGGihsa:84971
    UCSCiuc002mov.5 human [Q86TL0-1]

    Organism-specific databases

    CTDi84971
    EuPathDBiHostDB:ENSG00000130734.9
    GeneCardsiATG4D
    HGNCiHGNC:20789 ATG4D
    HPAiHPA067683
    MIMi611340 gene
    neXtProtiNX_Q86TL0
    OpenTargetsiENSG00000130734
    PharmGKBiPA134907475
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2674 Eukaryota
    ENOG410XPQ0 LUCA
    GeneTreeiENSGT00530000063000
    HOGENOMiHOG000294192
    HOVERGENiHBG050537
    InParanoidiQ86TL0
    KOiK08342
    OMAiNREHHEA
    OrthoDBiEOG091G065S
    PhylomeDBiQ86TL0
    TreeFamiTF314847

    Enzyme and pathway databases

    ReactomeiR-HSA-1632852 Macroautophagy

    Miscellaneous databases

    ChiTaRSiATG4D human
    GenomeRNAii84971
    PROiPR:Q86TL0
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000130734 Expressed in 197 organ(s), highest expression level in testis
    CleanExiHS_ATG4D
    ExpressionAtlasiQ86TL0 baseline and differential
    GenevisibleiQ86TL0 HS

    Family and domain databases

    InterProiView protein in InterPro
    IPR038765 Papain_like_cys_pep_sf
    IPR005078 Peptidase_C54
    PANTHERiPTHR22624 PTHR22624, 1 hit
    PfamiView protein in Pfam
    PF03416 Peptidase_C54, 1 hit
    SUPFAMiSSF54001 SSF54001, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiATG4D_HUMAN
    AccessioniPrimary (citable) accession number: Q86TL0
    Secondary accession number(s): Q969K0
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 15, 2005
    Last sequence update: June 1, 2003
    Last modified: November 7, 2018
    This is version 127 of the entry and version 1 of the sequence. See 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. SIMILARITY comments
      Index of protein domains and families
    2. Peptidase families
      Classification of peptidase families and list of entries
    3. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    4. Human chromosome 19
      Human chromosome 19: entries, gene names and cross-references to MIM
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