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Protein

Cysteine protease ATG4A

Gene

ATG4A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cysteine protease required for the cytoplasm to vacuole transport (Cvt) and autophagy. Cleaves the C-terminal amino acid of ATG8 family proteins 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. Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP. Has also an activity of delipidating enzyme for the PE-conjugated forms.6 Publications

Activity regulationi

Inhibited by N-ethylmaleimide. Redox-regulated during autophagy since reducing conditions activate ATG4A whereas an oxidizing environment such as the presence of H2O2 inhibits its activity.2 Publications

Kineticsi

  1. KM=33.9 µM for MAP1LC3B2 Publications
  2. KM=20.8 µM for GABARAP2 Publications
  3. KM=36.7 µM for GABARAPL12 Publications
  4. KM=15.7 µM for GABARAPL22 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei77NucleophileBy similarity1
    Active sitei279Sequence analysis1
    Active sitei281By similarity1

    GO - Molecular functioni

    • cysteine-type endopeptidase activity Source: GO_Central
    • cysteine-type peptidase activity Source: UniProtKB

    GO - Biological processi

    Keywordsi

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

    Enzyme and pathway databases

    ReactomeiR-HSA-1632852 Macroautophagy

    Protein family/group databases

    MEROPSiC54.002

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cysteine protease ATG4A (EC:3.4.22.-)
    Alternative name(s):
    AUT-like 2 cysteine endopeptidase
    Autophagin-2
    Autophagy-related cysteine endopeptidase 2
    Autophagy-related protein 4 homolog A
    Short name:
    hAPG4A
    Gene namesi
    Name:ATG4A
    Synonyms:APG4A, AUTL2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome X

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000101844.17
    HGNCiHGNC:16489 ATG4A
    MIMi300663 gene
    neXtProtiNX_Q8WYN0

    Subcellular locationi

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi81C → A: Reduces the redox sensitivity and retains activity in presence of H(2)O(2). 1 Publication1

    Organism-specific databases

    DisGeNETi115201
    OpenTargetsiENSG00000101844
    PharmGKBiPA25184

    Polymorphism and mutation databases

    BioMutaiATG4A
    DMDMi61211859

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002158381 – 398Cysteine protease ATG4AAdd BLAST398

    Proteomic databases

    EPDiQ8WYN0
    MaxQBiQ8WYN0
    PaxDbiQ8WYN0
    PeptideAtlasiQ8WYN0
    PRIDEiQ8WYN0
    ProteomicsDBi75173
    75174 [Q8WYN0-2]
    75175 [Q8WYN0-3]
    75176 [Q8WYN0-5]

    PTM databases

    iPTMnetiQ8WYN0
    PhosphoSitePlusiQ8WYN0

    Expressioni

    Tissue specificityi

    Widely expressed, at a low level, and the highest expression is observed in skeletal muscle and brain. Also detected in fetal liver.2 Publications

    Gene expression databases

    BgeeiENSG00000101844 Expressed in 213 organ(s), highest expression level in biceps brachii
    ExpressionAtlasiQ8WYN0 baseline and differential
    GenevisibleiQ8WYN0 HS

    Organism-specific databases

    HPAiHPA036374
    HPA064759

    Interactioni

    Binary interactionsi

    Protein-protein interaction databases

    BioGridi125418, 15 interactors
    IntActiQ8WYN0, 9 interactors
    MINTiQ8WYN0
    STRINGi9606.ENSP00000361306

    Structurei

    Secondary structure

    1398
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ8WYN0
    SMRiQ8WYN0
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ8WYN0

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the peptidase C54 family.Curated

    Phylogenomic databases

    eggNOGiKOG2674 Eukaryota
    ENOG410XPQ0 LUCA
    GeneTreeiENSGT00530000063000
    HOVERGENiHBG050536
    InParanoidiQ8WYN0
    KOiK08342
    OMAiACCPAWK
    OrthoDBiEOG091G0995
    PhylomeDBiQ8WYN0
    TreeFamiTF314847

    Family and domain databases

    InterProiView protein in InterPro
    IPR033474 ATG4A
    IPR038765 Papain_like_cys_pep_sf
    IPR005078 Peptidase_C54
    PANTHERiPTHR22624 PTHR22624, 1 hit
    PTHR22624:SF35 PTHR22624:SF35, 1 hit
    PfamiView protein in Pfam
    PF03416 Peptidase_C54, 1 hit
    SUPFAMiSSF54001 SSF54001, 1 hit

    Sequences (4+)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 4 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

    Isoform 1 (identifier: Q8WYN0-1) [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
    MESVLSKYED QITIFTDYLE EYPDTDELVW ILGKQHLLKT EKSKLLSDIS
    60 70 80 90 100
    ARLWFTYRRK FSPIGGTGPS SDAGWGCMLR CGQMMLAQAL ICRHLGRDWS
    110 120 130 140 150
    WEKQKEQPKE YQRILQCFLD RKDCCYSIHQ MAQMGVGEGK SIGEWFGPNT
    160 170 180 190 200
    VAQVLKKLAL FDEWNSLAVY VSMDNTVVIE DIKKMCRVLP LSADTAGDRP
    210 220 230 240 250
    PDSLTASNQS KGTSAYCSAW KPLLLIVPLR LGINQINPVY VDAFKECFKM
    260 270 280 290 300
    PQSLGALGGK PNNAYYFIGF LGDELIFLDP HTTQTFVDTE ENGTVNDQTF
    310 320 330 340 350
    HCLQSPQRMN ILNLDPSVAL GFFCKEEKDF DNWCSLVQKE ILKENLRMFE
    360 370 380 390
    LVQKHPSHWP PFVPPAKPEV TTTGAEFIDS TEQLEEFDLE EDFEILSV
    Length:398
    Mass (Da):45,378
    Last modified:March 1, 2002 - v1
    Checksum:i3BE892E22E432151
    GO
    Isoform 2 (identifier: Q8WYN0-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         211-272: Missing.

    Show »
    Length:336
    Mass (Da):38,601
    Checksum:i61D7819B73A0D8A9
    GO
    Isoform 3 (identifier: Q8WYN0-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-77: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:321
    Mass (Da):36,533
    Checksum:i5F6CAD07A44EC130
    GO
    Isoform 4 (identifier: Q8WYN0-5) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         41-64: Missing.

    Note: Gene prediction based on EST data.
    Show »
    Length:374
    Mass (Da):42,453
    Checksum:i4BB385D3C84939CB
    GO

    Computationally mapped potential isoform sequencesi

    There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    G5E979G5E979_HUMAN
    Cysteine protease
    ATG4A hCG_21686
    231Annotation score:
    A0A0A0MT61A0A0A0MT61_HUMAN
    Cysteine protease
    ATG4A
    202Annotation score:
    H7BYM2H7BYM2_HUMAN
    Cysteine protease
    ATG4A
    312Annotation score:
    F8W7J2F8W7J2_HUMAN
    Cysteine protease ATG4A
    ATG4A
    47Annotation score:

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti49I → Y in AAH41862 (PubMed:15489334).Curated1
    Sequence conflicti218S → T in CAC69076 (Ref. 3) Curated1
    Sequence conflicti218S → T in CAC69077 (Ref. 3) Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0259021 – 77Missing in isoform 3. 1 PublicationAdd BLAST77
    Alternative sequenceiVSP_03049941 – 64Missing in isoform 4. CuratedAdd BLAST24
    Alternative sequenceiVSP_013025211 – 272Missing in isoform 2. 1 PublicationAdd BLAST62

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ504651 mRNA Translation: CAD43218.1
    AB066214 mRNA Translation: BAB83889.1
    AJ320508 mRNA Translation: CAC69076.1
    AJ320509 mRNA Translation: CAC69077.1
    AK314429 mRNA Translation: BAG37044.1
    AL031177 Genomic DNA No translation available.
    CH471120 Genomic DNA Translation: EAX02689.1
    CH471120 Genomic DNA Translation: EAX02691.1
    CH471120 Genomic DNA Translation: EAX02693.1
    BC041862 mRNA Translation: AAH41862.1
    BC061696 mRNA Translation: AAH61696.1
    CCDSiCCDS14538.1 [Q8WYN0-1]
    CCDS14539.1 [Q8WYN0-2]
    RefSeqiNP_001308216.1, NM_001321287.1 [Q8WYN0-3]
    NP_001308217.1, NM_001321288.1 [Q8WYN0-3]
    NP_001308218.1, NM_001321289.1
    NP_443168.2, NM_052936.4 [Q8WYN0-1]
    NP_840054.1, NM_178270.3 [Q8WYN0-2]
    NP_840055.1, NM_178271.2 [Q8WYN0-3]
    XP_011529144.1, XM_011530842.1 [Q8WYN0-3]
    UniGeneiHs.8763

    Genome annotation databases

    EnsembliENST00000345734; ENSP00000298131; ENSG00000101844 [Q8WYN0-2]
    ENST00000372232; ENSP00000361306; ENSG00000101844 [Q8WYN0-1]
    GeneIDi115201
    KEGGihsa:115201
    UCSCiuc004enr.4 human [Q8WYN0-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ504651 mRNA Translation: CAD43218.1
    AB066214 mRNA Translation: BAB83889.1
    AJ320508 mRNA Translation: CAC69076.1
    AJ320509 mRNA Translation: CAC69077.1
    AK314429 mRNA Translation: BAG37044.1
    AL031177 Genomic DNA No translation available.
    CH471120 Genomic DNA Translation: EAX02689.1
    CH471120 Genomic DNA Translation: EAX02691.1
    CH471120 Genomic DNA Translation: EAX02693.1
    BC041862 mRNA Translation: AAH41862.1
    BC061696 mRNA Translation: AAH61696.1
    CCDSiCCDS14538.1 [Q8WYN0-1]
    CCDS14539.1 [Q8WYN0-2]
    RefSeqiNP_001308216.1, NM_001321287.1 [Q8WYN0-3]
    NP_001308217.1, NM_001321288.1 [Q8WYN0-3]
    NP_001308218.1, NM_001321289.1
    NP_443168.2, NM_052936.4 [Q8WYN0-1]
    NP_840054.1, NM_178270.3 [Q8WYN0-2]
    NP_840055.1, NM_178271.2 [Q8WYN0-3]
    XP_011529144.1, XM_011530842.1 [Q8WYN0-3]
    UniGeneiHs.8763

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2FUYmodel-A1-398[»]
    2P82X-ray2.10A/B/C/D23-359[»]
    ProteinModelPortaliQ8WYN0
    SMRiQ8WYN0
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi125418, 15 interactors
    IntActiQ8WYN0, 9 interactors
    MINTiQ8WYN0
    STRINGi9606.ENSP00000361306

    Protein family/group databases

    MEROPSiC54.002

    PTM databases

    iPTMnetiQ8WYN0
    PhosphoSitePlusiQ8WYN0

    Polymorphism and mutation databases

    BioMutaiATG4A
    DMDMi61211859

    Proteomic databases

    EPDiQ8WYN0
    MaxQBiQ8WYN0
    PaxDbiQ8WYN0
    PeptideAtlasiQ8WYN0
    PRIDEiQ8WYN0
    ProteomicsDBi75173
    75174 [Q8WYN0-2]
    75175 [Q8WYN0-3]
    75176 [Q8WYN0-5]

    Protocols and materials databases

    DNASUi115201
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000345734; ENSP00000298131; ENSG00000101844 [Q8WYN0-2]
    ENST00000372232; ENSP00000361306; ENSG00000101844 [Q8WYN0-1]
    GeneIDi115201
    KEGGihsa:115201
    UCSCiuc004enr.4 human [Q8WYN0-1]

    Organism-specific databases

    CTDi115201
    DisGeNETi115201
    EuPathDBiHostDB:ENSG00000101844.17
    GeneCardsiATG4A
    HGNCiHGNC:16489 ATG4A
    HPAiHPA036374
    HPA064759
    MIMi300663 gene
    neXtProtiNX_Q8WYN0
    OpenTargetsiENSG00000101844
    PharmGKBiPA25184
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2674 Eukaryota
    ENOG410XPQ0 LUCA
    GeneTreeiENSGT00530000063000
    HOVERGENiHBG050536
    InParanoidiQ8WYN0
    KOiK08342
    OMAiACCPAWK
    OrthoDBiEOG091G0995
    PhylomeDBiQ8WYN0
    TreeFamiTF314847

    Enzyme and pathway databases

    ReactomeiR-HSA-1632852 Macroautophagy

    Miscellaneous databases

    EvolutionaryTraceiQ8WYN0
    GeneWikiiATG4A
    GenomeRNAii115201
    PROiPR:Q8WYN0
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000101844 Expressed in 213 organ(s), highest expression level in biceps brachii
    ExpressionAtlasiQ8WYN0 baseline and differential
    GenevisibleiQ8WYN0 HS

    Family and domain databases

    InterProiView protein in InterPro
    IPR033474 ATG4A
    IPR038765 Papain_like_cys_pep_sf
    IPR005078 Peptidase_C54
    PANTHERiPTHR22624 PTHR22624, 1 hit
    PTHR22624:SF35 PTHR22624:SF35, 1 hit
    PfamiView protein in Pfam
    PF03416 Peptidase_C54, 1 hit
    SUPFAMiSSF54001 SSF54001, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiATG4A_HUMAN
    AccessioniPrimary (citable) accession number: Q8WYN0
    Secondary accession number(s): A6NCH2
    , B2RAZ7, D3DUY0, O95534, Q5JYY9, Q5JYZ0, Q86VE5, Q96KQ0, Q96KQ1
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 15, 2005
    Last sequence update: March 1, 2002
    Last modified: November 7, 2018
    This is version 134 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

    3D-structure, 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 X
      Human chromosome X: entries, gene names and cross-references to MIM
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
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