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Q8WYN0 (ATG4A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:ATG4A
Synonyms:APG4A, AUTL2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length398 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12

Enzyme regulation

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. Ref.8 Ref.9

Subcellular location

Cytoplasm By similarity.

Tissue specificity

Widely expressed, at a low level, and the highest expression is observed in skeletal muscle and brain. Also detected in fetal liver. Ref.1 Ref.2

Sequence similarities

Belongs to the peptidase C54 family.

Biophysicochemical properties

Kinetic parameters:

KM=33.9 µM for MAP1LC3B Ref.10 Ref.12

KM=20.8 µM for GABARAP

KM=36.7 µM for GABARAPL1

KM=15.7 µM for GABARAPL2

Ontologies

Keywords
   Biological processAutophagy
Protein transport
Transport
Ubl conjugation pathway
   Cellular componentCytoplasm
   Coding sequence diversityAlternative splicing
   Molecular functionHydrolase
Protease
Thiol protease
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processautophagy

Inferred from electronic annotation. Source: UniProtKB-KW

protein transport

Inferred from electronic annotation. Source: UniProtKB-KW

proteolysis

Inferred from direct assay Ref.8Ref.2. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity Ref.1. Source: UniProtKB

   Molecular_functioncysteine-type peptidase activity

Inferred from direct assay Ref.8Ref.2. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q8WYN0-1)

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.
Isoform 2 (identifier: Q8WYN0-2)

The sequence of this isoform differs from the canonical sequence as follows:
     211-272: Missing.
Isoform 3 (identifier: Q8WYN0-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-77: Missing.
Note: No experimental confirmation available.
Isoform 4 (identifier: Q8WYN0-5)

The sequence of this isoform differs from the canonical sequence as follows:
     41-64: Missing.
Note: Gene prediction based on EST data.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 398398Cysteine protease ATG4A
PRO_0000215838

Sites

Active site771Nucleophile By similarity
Active site2791 Potential
Active site2811 By similarity

Natural variations

Alternative sequence1 – 7777Missing in isoform 3.
VSP_025902
Alternative sequence41 – 6424Missing in isoform 4.
VSP_030499
Alternative sequence211 – 27262Missing in isoform 2.
VSP_013025

Experimental info

Mutagenesis811C → A: Reduces the redox sensitivity and retains activity in presence of H(2)O(2). Ref.9
Sequence conflict491I → Y in AAH41862. Ref.7
Sequence conflict2181S → T in CAC69076. Ref.3
Sequence conflict2181S → T in CAC69077. Ref.3

Secondary structure

.......................................................... 398
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified March 1, 2002. Version 1.
Checksum: 3BE892E22E432151

FASTA39845,378
        10         20         30         40         50         60 
MESVLSKYED QITIFTDYLE EYPDTDELVW ILGKQHLLKT EKSKLLSDIS ARLWFTYRRK 

        70         80         90        100        110        120 
FSPIGGTGPS SDAGWGCMLR CGQMMLAQAL ICRHLGRDWS WEKQKEQPKE YQRILQCFLD 

       130        140        150        160        170        180 
RKDCCYSIHQ MAQMGVGEGK SIGEWFGPNT VAQVLKKLAL FDEWNSLAVY VSMDNTVVIE 

       190        200        210        220        230        240 
DIKKMCRVLP LSADTAGDRP PDSLTASNQS KGTSAYCSAW KPLLLIVPLR LGINQINPVY 

       250        260        270        280        290        300 
VDAFKECFKM PQSLGALGGK PNNAYYFIGF LGDELIFLDP HTTQTFVDTE ENGTVNDQTF 

       310        320        330        340        350        360 
HCLQSPQRMN ILNLDPSVAL GFFCKEEKDF DNWCSLVQKE ILKENLRMFE LVQKHPSHWP 

       370        380        390 
PFVPPAKPEV TTTGAEFIDS TEQLEEFDLE EDFEILSV 

« Hide

Isoform 2 [UniParc].

Checksum: 61D7819B73A0D8A9
Show »

FASTA33638,601
Isoform 3 [UniParc].

Checksum: 5F6CAD07A44EC130
Show »

FASTA32136,533
Isoform 4 [UniParc].

Checksum: 4BB385D3C84939CB
Show »

FASTA37442,453

References

« Hide 'large scale' references
[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: Ovary.
[2]"LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation."
Kabeya Y., Mizushima N., Yamamoto A., Oshitani-Okamoto S., Ohsumi Y., Yoshimori T.
J. Cell Sci. 117:2805-2812(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN GABARAPL2; GABARAP AND MAP1LC3 CLEAVAGE, TISSUE SPECIFICITY.
[3]"Cloning and sequencing of a second human homologue of the yeast Apg4 cysteine endopeptidase involved in autophagy."
Chen J.M., Barrett A.J.
Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
Tissue: Prostate and Testis.
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]"The DNA sequence of the human X chromosome."
Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. expand/collapse author list , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R.
Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"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 3).
Tissue: Kidney and Testis.
[8]"The COOH terminus of GATE-16, an intra-Golgi transport modulator, is cleaved by the human cysteine protease HsApg4A."
Scherz-Shouval R., Sagiv Y., Shorer H., Elazar Z.
J. Biol. Chem. 278:14053-14058(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GABARAPL2 CLEAVAGE, ENZYME REGULATION.
[9]"Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4."
Scherz-Shouval R., Shvets E., Fass E., Shorer H., Gil L., Elazar Z.
EMBO J. 26:1749-1760(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, MUTAGENESIS OF CYS-81.
[10]"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.
[11]"High-throughput fluorescence assay for small-molecule inhibitors of autophagins/Atg4."
Shu C.W., Madiraju C., Zhai D., Welsh K., Diaz P., Sergienko E., Sano R., Reed J.C.
J. Biomol. Screen. 16:174-182(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"A high-throughput FRET-based assay for determination of Atg4 activity."
Li M., Chen X., Ye Q.Z., Vogt A., Yin X.M.
Autophagy 8:401-412(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[13]"Human cysteine protease ATG4A."
Walker J.R., Davis T., Mujib S., Butler-Cole C., Finerty P.J., Weigelt J., Sundstrom M., Arrowsmith C.H., Edwards A.M., Bochkarev A., Dhe-Paganon S.
Submitted (MAR-2007) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 23-359.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_443168.2. NM_052936.3.
NP_840054.1. NM_178270.2.
XP_005262121.1. XM_005262064.1.
UniGeneHs.8763.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2FUYmodel-A1-398[»]
2P82X-ray2.10A/B/C/D23-359[»]
ProteinModelPortalQ8WYN0.
SMRQ8WYN0. Positions 26-359.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid125418. 2 interactions.
IntActQ8WYN0. 2 interactions.
MINTMINT-3048289.

Protein family/group databases

MEROPSC54.002.

Polymorphism databases

DMDM61211859.

Proteomic databases

PaxDbQ8WYN0.
PRIDEQ8WYN0.

Protocols and materials databases

DNASU115201.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000345734; ENSP00000298131; ENSG00000101844. [Q8WYN0-2]
ENST00000372232; ENSP00000361306; ENSG00000101844. [Q8WYN0-1]
ENST00000372254; ENSP00000361328; ENSG00000101844. [Q8WYN0-5]
GeneID115201.
KEGGhsa:115201.
UCSCuc004enr.3. human. [Q8WYN0-1]
uc004ent.3. human. [Q8WYN0-2]

Organism-specific databases

CTD115201.
GeneCardsGC0XP107334.
HGNCHGNC:16489. ATG4A.
HPAHPA036374.
MIM300663. gene.
neXtProtNX_Q8WYN0.
PharmGKBPA25184.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG239662.
HOVERGENHBG050536.
InParanoidQ8WYN0.
KOK08342.
OMAKGTSAYC.
OrthoDBEOG73V6KD.
PhylomeDBQ8WYN0.
TreeFamTF314847.

Gene expression databases

ArrayExpressQ8WYN0.
BgeeQ8WYN0.
GenevestigatorQ8WYN0.

Family and domain databases

InterProIPR005078. Peptidase_C54.
[Graphical view]
PANTHERPTHR22624. PTHR22624. 1 hit.
PfamPF03416. Peptidase_C54. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ8WYN0.
GeneWikiATG4A.
GenomeRNAi115201.
NextBio79530.
PROQ8WYN0.
SOURCESearch...

Entry information

Entry nameATG4A_HUMAN
AccessionPrimary (citable) accession number: Q8WYN0
Secondary accession number(s): A6NCH2 expand/collapse secondary AC list , B2RAZ7, D3DUY0, O95534, Q5JYY9, Q5JYZ0, Q86VE5, Q96KQ0, Q96KQ1
Entry history
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: March 1, 2002
Last modified: April 16, 2014
This is version 99 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome X

Human chromosome X: entries, gene names and cross-references to MIM