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Protein

Cysteine protease ATG4A

Gene

ATG4A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

Enzyme 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

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase, Protease, Thiol protease

    Keywords - Biological processi

    Autophagy, Protein transport, Transport, Ubl conjugation pathway

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000101844-MONOMER.
    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

    HGNCiHGNC:16489. ATG4A.

    Subcellular locationi

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • cytosol Source: GO_Central
    Complete GO annotation...

    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.

    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.
    ExpressionAtlasiQ8WYN0. baseline and differential.
    GenevisibleiQ8WYN0. HS.

    Organism-specific databases

    HPAiHPA036374.
    HPA064759.

    Interactioni

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    CDKL3Q8IVW43EBI-3044060,EBI-3919850
    GABARAPL1Q9H0R85EBI-3044060,EBI-746969

    Protein-protein interaction databases

    BioGridi125418. 15 interactors.
    IntActiQ8WYN0. 9 interactors.
    MINTiMINT-3048289.
    STRINGi9606.ENSP00000361306.

    Structurei

    Secondary structure

    1398
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi28 – 31Combined sources4
    Beta strandi34 – 37Combined sources4
    Turni38 – 41Combined sources4
    Helixi42 – 50Combined sources9
    Beta strandi57 – 61Combined sources5
    Turni64 – 67Combined sources4
    Turni73 – 75Combined sources3
    Helixi77 – 94Combined sources18
    Helixi110 – 116Combined sources7
    Beta strandi119 – 121Combined sources3
    Helixi128 – 136Combined sources9
    Turni137 – 139Combined sources3
    Helixi148 – 159Combined sources12
    Turni163 – 165Combined sources3
    Beta strandi168 – 171Combined sources4
    Beta strandi176 – 178Combined sources3
    Helixi179 – 186Combined sources8
    Beta strandi223 – 230Combined sources8
    Beta strandi233 – 235Combined sources3
    Helixi238 – 240Combined sources3
    Helixi241 – 249Combined sources9
    Beta strandi253 – 260Combined sources8
    Beta strandi263 – 271Combined sources9
    Beta strandi274 – 278Combined sources5
    Beta strandi282 – 285Combined sources4
    Helixi298 – 300Combined sources3
    Beta strandi307 – 310Combined sources4
    Helixi311 – 313Combined sources3
    Beta strandi316 – 326Combined sources11
    Helixi327 – 340Combined sources14
    Turni341 – 343Combined sources3
    Beta strandi344 – 346Combined sources3
    Beta strandi348 – 354Combined sources7

    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...

    Miscellaneous databases

    EvolutionaryTraceiQ8WYN0.

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the peptidase C54 family.Curated

    Phylogenomic databases

    eggNOGiKOG2674. Eukaryota.
    ENOG410XPQ0. LUCA.
    GeneTreeiENSGT00530000063000.
    HOVERGENiHBG050536.
    InParanoidiQ8WYN0.
    KOiK08342.
    OMAiTAADVWF.
    OrthoDBiEOG091G0995.
    PhylomeDBiQ8WYN0.
    TreeFamiTF314847.

    Family and domain databases

    InterProiIPR033474. ATG4A.
    IPR005078. Peptidase_C54.
    [Graphical view]
    PANTHERiPTHR22624. PTHR22624. 1 hit.
    PTHR22624:SF35. PTHR22624:SF35. 1 hit.
    PfamiPF03416. Peptidase_C54. 1 hit.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

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

    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

    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. Translation: CAI43137.1.
    AL031177 Genomic DNA. Translation: CAI43138.1.
    AL031177 Genomic DNA. Translation: CAI43141.1.
    AL031177 Genomic DNA. Translation: CAI43142.1.
    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

    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. Translation: CAI43137.1.
    AL031177 Genomic DNA. Translation: CAI43138.1.
    AL031177 Genomic DNA. Translation: CAI43141.1.
    AL031177 Genomic DNA. Translation: CAI43142.1.
    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.
    MINTiMINT-3048289.
    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.

    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.
    GeneCardsiATG4A.
    HGNCiHGNC:16489. ATG4A.
    HPAiHPA036374.
    HPA064759.
    MIMi300663. gene.
    neXtProtiNX_Q8WYN0.
    OpenTargetsiENSG00000101844.
    PharmGKBiPA25184.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2674. Eukaryota.
    ENOG410XPQ0. LUCA.
    GeneTreeiENSGT00530000063000.
    HOVERGENiHBG050536.
    InParanoidiQ8WYN0.
    KOiK08342.
    OMAiTAADVWF.
    OrthoDBiEOG091G0995.
    PhylomeDBiQ8WYN0.
    TreeFamiTF314847.

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000101844-MONOMER.
    ReactomeiR-HSA-1632852. Macroautophagy.

    Miscellaneous databases

    EvolutionaryTraceiQ8WYN0.
    GeneWikiiATG4A.
    GenomeRNAii115201.
    PROiQ8WYN0.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000101844.
    ExpressionAtlasiQ8WYN0. baseline and differential.
    GenevisibleiQ8WYN0. HS.

    Family and domain databases

    InterProiIPR033474. ATG4A.
    IPR005078. Peptidase_C54.
    [Graphical view]
    PANTHERiPTHR22624. PTHR22624. 1 hit.
    PTHR22624:SF35. PTHR22624:SF35. 1 hit.
    PfamiPF03416. Peptidase_C54. 1 hit.
    [Graphical view]
    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 historyi
    Integrated into UniProtKB/Swiss-Prot: March 15, 2005
    Last sequence update: March 1, 2002
    Last modified: November 30, 2016
    This is version 124 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

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome X
      Human chromosome X: 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. Peptidase families
      Classification of peptidase families and list of entries
    5. SIMILARITY comments
      Index of protein domains and families

    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 one 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.