UniProt Accession

 SET_HUMAN; Q01105; A5A5H4; A6NGV1; B4DUE2; Q15541; Q5VXV1; Q5VXV2; Q6FHZ5 

Genbank Protein ID

 M93651; X75091; D45198; U51924; AY349172; CR536543; CR542050; AK223556; AK300609; AL356481; AL359678; BC032749; EF534308 

Genbank Nucleotide ID

 AAA60318.1; CAA52982.1; BAA08139.1; AAC50460.1; AAQ79833.1; CAG38780.1; CAG46847.1; BAD97276.1; BAG62304.1; CAH71410.1; AAH32749.1; ABP96841.1 

Protein Name

 Protein SET 

Protein Synonyms/Alias

 HLA-DR-associated protein II; Inhibitor of granzyme A-activated DNase; IGAAD; PHAPII; Phosphatase 2A inhibitor I2PP2A; I-2PP2A; Template-activating factor I; TAF-I 

Gene Name

 SET 

Gene Synonyms/Alias

  

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
68	QASEEILKVEQKYNK	acetylation	[1]
68	QASEEILKVEQKYNK	ubiquitination	[2, 3, 4]
72	EILKVEQKYNKLRQP	acetylation	[1, 5]
83	LRQPFFQKRSELIAK	acetylation	[5, 6]
83	LRQPFFQKRSELIAK	ubiquitination	[3, 4, 5, 7, 8]
132	VTEFEDIKSGYRIDF	acetylation	[1, 5, 6]
132	VTEFEDIKSGYRIDF	ubiquitination	[2, 3, 4, 5, 7, 9, 10, 11]
150	ENPYFENKVLSKEFH	acetylation	[1, 6]
150	ENPYFENKVLSKEFH	ubiquitination	[2, 4, 5, 7, 8, 10, 11, 12]
154	FENKVLSKEFHLNES	acetylation	[5]
154	FENKVLSKEFHLNES	ubiquitination	[2, 3, 4, 5, 7, 8, 9, 12, 13, 14]
167	ESGDPSSKSTEIKWK	acetylation	[1]
167	ESGDPSSKSTEIKWK	ubiquitination	[2, 3, 4, 5, 7, 8]
172	SSKSTEIKWKSGKDL	acetylation	[5, 6, 15]
172	SSKSTEIKWKSGKDL	ubiquitination	[5, 7, 8]

Reference

 [1] Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3.
 Sol EM, Wagner SA, Weinert BT, Kumar A, Kim HS, Deng CX, Choudhary C.
 PLoS One. 2012;7(12):e50545. [PMID: 23236377]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [4] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]
 [5] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [6] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [7] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [8] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [9] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [10] Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin.
 Oshikawa K, Matsumoto M, Oyamada K, Nakayama KI.
 J Proteome Res. 2012 Feb 3;11(2):796-807. [PMID: 22053931]
 [11] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [12] Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level.
 Danielsen JM, Sylvestersen KB, Bekker-Jensen S, Szklarczyk D, Poulsen JW, Horn H, Jensen LJ, Mailand N, Nielsen ML.
 Mol Cell Proteomics. 2011 Mar;10(3):M110.003590. [PMID: 21139048]
 [13] Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry.
 Meierhofer D, Wang X, Huang L, Kaiser P.
 J Proteome Res. 2008 Oct;7(10):4566-76. [PMID: 18781797]
 [14] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [15] Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response.
 Beli P, Lukashchuk N, Wagner SA, Weinert BT, Olsen JV, Baskcomb L, Mann M, Jackson SP, Choudhary C.
 Mol Cell. 2012 Apr 27;46(2):212-25. [PMID: 22424773] 

Functional Description

 Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T- lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher. 

Sequence Annotation

 REGION 31 78 Dimerization.
 REGION 79 225 Earmuff domain.
 MOD_RES 2 2 N,N,N-trimethylalanine (By similarity).
 MOD_RES 7 7 Phosphoserine.
 MOD_RES 132 132 N6-acetyllysine.
 MOD_RES 146 146 Phosphotyrosine (By similarity).
 MOD_RES 150 150 N6-acetyllysine.
 MOD_RES 172 172 N6-acetyllysine.
 CROSSLNK 154 154 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Acetylation; Alternative splicing; Chaperone; Chromosomal rearrangement; Complete proteome; Cytoplasm; Direct protein sequencing; DNA-binding; Endoplasmic reticulum; Isopeptide bond; Methylation; Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 290 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
 GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
 GO:0043234; C:protein complex; IDA:UniProtKB.
 GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
 GO:0042393; F:histone binding; TAS:UniProtKB.
 GO:0004864; F:protein phosphatase inhibitor activity; TAS:ProtInc.
 GO:0008601; F:protein phosphatase type 2A regulator activity; TAS:UniProtKB.
 GO:0006260; P:DNA replication; TAS:ProtInc.
 GO:0010467; P:gene expression; TAS:Reactome.
 GO:0016071; P:mRNA metabolic process; TAS:Reactome.
 GO:0035067; P:negative regulation of histone acetylation; TAS:UniProtKB.
 GO:0043524; P:negative regulation of neuron apoptotic process; IGI:MGI.
 GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
 GO:0006913; P:nucleocytoplasmic transport; NAS:UniProtKB.
 GO:0006334; P:nucleosome assembly; TAS:ProtInc.
 GO:0006337; P:nucleosome disassembly; TAS:UniProtKB. 

Interpro

 IPR002164; NAP_family. 

Pfam

 PF00956; NAP 

SMART

  

PROSITE

  

PRINTS