Reviewed, UniProtKB/Swiss-Prot Q8WYN0 (ATG4A_HUMAN)

Names and origin

Protein names

Recommended name:
    Cysteine protease ATG4A
    EC=3.4.22.-
Alternative name(s):
    Autophagy-related protein 4 homolog A
      Short name=hAPG4A
    Autophagin-2
    Autophagy-related cysteine endopeptidase 2
    AUT-like 2 cysteine endopeptidase

Gene names

Name:	ATG4A
Synonyms:	APG4A, AUTL2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	398 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Cysteine protease required for autophagy, which cleaves the C-terminal part of either MAP1LC3, GABARAPL2 or GABARAP, allowing the liberation of form I. A subpopulation of form I is subsequently converted to a smaller form (form II). Form II, with a revealed C-terminal glycine, is considered to be the phosphatidylethanolamine (PE)-conjugated form, and has the capacity for the binding to autophagosomes. Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP. Ref.2 Ref.8
Enzyme regulation	Inhibited by N-ethylmaleimide.
Subcellular location	Cytoplasm Probable.
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.2 Ref.1
Sequence similarities	Belongs to the peptidase C54 family.

Ontologies

Keywords
Biological process	Autophagy Protein transport Transport Ubl conjugation pathway
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	autophagy Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW protein targeting to vacuole Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytoplasm Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB microtubule associated complex Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	cysteine-type peptidase activity Ref.2 Ref.8 Inferred from direct assay. Source: UniProtKB microtubule binding Ref.1 Inferred from sequence or structural similarity. 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 398

398

Cysteine protease ATG4A

PRO_0000215838

Sites

Active site

77

1

Nucleophile By similarity

Active site

279

1

Potential

Active site

281

1

By similarity

Amino acid modifications

Modified residue

47

1

Phosphoserine Ref.9

Natural variations

Alternative sequence

1 – 77

77

Missing in isoform 3.

VSP_025902

Alternative sequence

41 – 64

24

Missing in isoform 4.

VSP_030499

Alternative sequence

211 – 272

62

Missing in isoform 2.

VSP_013025

Experimental info

Sequence conflict

49

1

I → Y in AAH41862. Ref.7

Sequence conflict

218

1

S → T in CAC69076. Ref.3

Sequence conflict

218

1

S → T in CAC69077. Ref.3

Secondary structure

1

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398

Helix Strand Turn

Details...

Beta strand

28 – 31

4

Beta strand

34 – 37

4

Turn

38 – 41

4

Helix

42 – 50

9

Beta strand

57 – 61

5

Turn

64 – 67

4

Turn

73 – 75

3

Helix

77 – 94

18

Helix

110 – 116

7

Beta strand

119 – 121

3

Helix

128 – 136

9

Turn

137 – 139

3

Helix

148 – 159

12

Turn

163 – 165

3

Beta strand

168 – 171

4

Beta strand

176 – 178

3

Helix

179 – 186

8

Beta strand

223 – 230

8

Beta strand

233 – 235

3

Helix

238 – 240

3

Helix

241 – 249

9

Beta strand

253 – 260

8

Beta strand

263 – 271

9

Beta strand

274 – 278

5

Beta strand

282 – 285

4

Helix

298 – 300

3

Beta strand

307 – 310

4

Helix

311 – 313

3

Beta strand

316 – 326

11

Helix

327 – 340

14

Turn

341 – 343

3

Beta strand

344 – 346

3

Beta strand

348 – 354

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2002. Version 1. Checksum: 3BE892E22E432151	FASTA	398	45,378
	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
	Isoform 2. Checksum: 61D7819B73A0D8A9	FASTA	336	38,601
	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 DELIFLDPHT TQTFVDTEEN GTVNDQTFHC 250 260 270 280 290 300 LQSPQRMNIL NLDPSVALGF FCKEEKDFDN WCSLVQKEIL KENLRMFELV QKHPSHWPPF 310 320 330 VPPAKPEVTT TGAEFIDSTE QLEEFDLEED FEILSV
	Isoform 3. Checksum: 5F6CAD07A44EC130	FASTA	321	36,533
	10 20 30 40 50 60 MLRCGQMMLA QALICRHLGR DWSWEKQKEQ PKEYQRILQC FLDRKDCCYS IHQMAQMGVG 70 80 90 100 110 120 EGKSIGEWFG PNTVAQVLKK LALFDEWNSL AVYVSMDNTV VIEDIKKMCR VLPLSADTAG 130 140 150 160 170 180 DRPPDSLTAS NQSKGTSAYC SAWKPLLLIV PLRLGINQIN PVYVDAFKEC FKMPQSLGAL 190 200 210 220 230 240 GGKPNNAYYF IGFLGDELIF LDPHTTQTFV DTEENGTVND QTFHCLQSPQ RMNILNLDPS 250 260 270 280 290 300 VALGFFCKEE KDFDNWCSLV QKEILKENLR MFELVQKHPS HWPPFVPPAK PEVTTTGAEF 310 320 IDSTEQLEEF DLEEDFEILS V
	Isoform 4. Checksum: 4BB385D3C84939CB	FASTA	374	42,453
	10 20 30 40 50 60 MESVLSKYED QITIFTDYLE EYPDTDELVW ILGKQHLLKT GGTGPSSDAG WGCMLRCGQM 70 80 90 100 110 120 MLAQALICRH LGRDWSWEKQ KEQPKEYQRI LQCFLDRKDC CYSIHQMAQM GVGEGKSIGE 130 140 150 160 170 180 WFGPNTVAQV LKKLALFDEW NSLAVYVSMD NTVVIEDIKK MCRVLPLSAD TAGDRPPDSL 190 200 210 220 230 240 TASNQSKGTS AYCSAWKPLL LIVPLRLGIN QINPVYVDAF KECFKMPQSL GALGGKPNNA 250 260 270 280 290 300 YYFIGFLGDE LIFLDPHTTQ TFVDTEENGT VNDQTFHCLQ SPQRMNILNL DPSVALGFFC 310 320 330 340 350 360 KEEKDFDNWC SLVQKEILKE NLRMFELVQK HPSHWPPFVP PAKPEVTTTG AEFIDSTEQL 370 EEFDLEEDFE ILSV

References

	« Hide 'large scale' referencesShow '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: 12446702] [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: 15169837] [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. , 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: 14702039] [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. , 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: 15772651] [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. , 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: 15489334] [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: 12473658] [Abstract] Cited for: FUNCTION IN GABARAPL2 CLEAVAGE.
[9]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, MASS SPECTROMETRY. Tissue: Epithelium.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.
BC041862 mRNA. Translation: AAH41862.1.
BC061696 mRNA. Translation: AAH61696.1.

IPI

IPI00064708.
IPI00292327.
IPI00328880.
IPI00640839.

RefSeq

NP_443168.2.
NP_840054.1.

UniGene

Hs.8763

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2FUY	model	-	A	1-398	[»]
2P82	X-ray	2.10	A/B/C/D	23-359	[»]

ModBase

Search...

Protein family/group databases

MEROPS

C54.002.

Proteomic databases

PRIDE

Q8WYN0.

Genome annotation databases

Ensembl

ENSG00000101844. Homo sapiens. [Contig view]

GeneID

115201.

KEGG

hsa:115201.

Organism-specific databases

GeneCards

GC0XP107221.

HGNC

HGNC:16489. ATG4A.

MIM

300663. gene.

PharmGKB

PA25184.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

Q8WYN0.

Gene expression databases

Bgee

Q8WYN0.

GermOnline

ENSG00000101844. Homo sapiens.

Family and domain databases

InterPro

IPR005078. Peptidase_C54.
[Graphical view]

PANTHER

PTHR22624. Peptidase_C54. 1 hit.

Pfam

PF03416. Peptidase_C54. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

79530.

SOURCE

Search...

Entry information

Entry name

ATG4A_HUMAN

Accession

Primary (citable) accession number: Q8WYN0
Secondary accession number(s): A6NCH2 , B2RAZ7, O95534, Q5JYY9, Q5JYZ0, Q86VE5, Q96KQ0, Q96KQ1

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	March 1, 2002
Last modified:	June 16, 2009
This is version 56 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)