Protein SET - Homo sapiens (Human)

Names and origin

Protein names

Recommended name:
    Protein SET
Alternative name(s):
    Phosphatase 2A inhibitor I2PP2A
      Short name=I-2PP2A
    Template-activating factor I
      Short name=TAF-I
    HLA-DR-associated protein II
    PHAPII
    Inhibitor of granzyme A-activated DNase
      Short name=IGAAD

Gene names

Name:

SET

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	290 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone binding. 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.
Subunit structure	Isoform 1 and isoform 2 interact directly with each other and with ANP32A within the tripartite INHAT (inhibitor of acetyltransferases) complex. Isoform 1 and isoform 2 interact also with histones. Isoform 2 is a component of the SET complex, which also contains ANP32A, APEX1, HMGB2 and NME1, but not NME2. Within this complex, directly interacts with NME1 and with HMGB2. Interacts with SETBP1.
Subcellular location	Cytoplasm › cytosol. Endoplasmic reticulum. Nucleus › nucleoplasm. Note= In the cytoplasm, found both in the cytosol and associated with the endoplasmic reticulum. Following CTL attack, moves rapidly to the nucleus, where it is found in the nucleoplasm, avoiding the nucleolus. Similar translocation to the nucleus is also observed for lymphocyte-activated killer cells after the addition of calcium. The SET complex is associated with the endoplasmic reticulum.
Tissue specificity	Widely expressed. Low levels in quiescent cells during serum starvation, contact inhibition or differentiation. Highly expressed in Wilms' tumor.
Domain	The C-terminal acidic domain mediates the inhibition of histone acetyltransferases and is required for the DNA replication stimulatory activity.
Post-translational modification	Isoform 2 is phosphorylated on Ser-15 and Thr-23. Isoform 2 is acetylated on Lys-11.
Involvement in disease	A chromosomal aberration involving SET is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with NUP214/CAN.
Sequence similarities	Belongs to the nucleosome assembly protein (NAP) family.

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Ontologies

Keywords
Cellular component	Cytoplasm Endoplasmic reticulum Nucleus
Coding sequence diversity	Alternative splicing Chromosomal rearrangement Polymorphism
Disease	Proto-oncogene
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	DNA replication Ref.3 Traceable author statement. Source: ProtInc negative regulation of histone acetylation Traceable author statement. Source: UniProtKB nucleocytoplasmic transport Non-traceable author statement. Source: UniProtKB nucleosome assembly Ref.1 Traceable author statement. Source: ProtInc nucleosome disassembly Traceable author statement. Source: UniProtKB
Cellular component	endoplasmic reticulum Inferred from direct assay. Source: UniProtKB nucleus Inferred from direct assay. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB
Molecular function	histone binding Traceable author statement. Source: UniProtKB protein phosphatase inhibitor activity Ref.4 Traceable author statement. Source: ProtInc protein phosphatase type 2A regulator activity Traceable author statement. Source: UniProtKB
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
CSNK2A1	P68400	1	EBI-1053182,EBI-347804
DGKE	P52429	1	EBI-1053182,EBI-1057499
Eef1a1	P10126	1	EBI-1053182,EBI-773865	From a different organism.
RGS20	O76081	1	EBI-1053182,EBI-1052678

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Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q01105-1)

Also known as: TAF-I alpha;

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: Q01105-2)

Also known as: TAF-I beta;

The sequence of this isoform differs from the canonical sequence as follows:
1-37: MAPKRQSPLPPQKKKPRPPPALGPEETSASAGLPKKG → MSAPAAKVSKKELNSNHDGADETS

Notes: Acetylated on Lys-11. Phosphorylated on Ser-15 and Thr-23.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Natural variant

4

1

P → Q: dbSNP rs1141138.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 290

290

Protein SET

PRO_0000185662

Regions

Compositional bias

239 – 290

52

Asp/Glu-rich (highly acidic)

Sites

Site

283 – 284

2

Breakpoint for translocation to form SET-CAN oncogene

Amino acid modifications

Modified residue

7

1

Phosphoserine

Modified residue

30

1

Phosphoserine By similarity

Modified residue

146

1

Phosphotyrosine By similarity

Natural variations

Alternative sequence

1 – 37

37

MAPKR…LPKKG → MSAPAAKVSKKELNSNHDGA DETS in isoform 2.

VSP_009868

Secondary structure

1

.

290

Helix Strand Turn

Details...

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Sequences

Sequence		Length	Mass (Da)
Isoform 1 (TAF-I alpha) [UniParc]. Last modified April 13, 2004. Version 3. Checksum: F4664118171EF230 Show »	FASTA	290	33,489
10 20 30 40 50 60 MAPKRQSPLP PQKKKPRPPP ALGPEETSAS AGLPKKGEKE QQEAIEHIDE VQNEIDRLNE 70 80 90 100 110 120 QASEEILKVE QKYNKLRQPF FQKRSELIAK IPNFWVTTFV NHPQVSALLG EEDEEALHYL 130 140 150 160 170 180 TRVEVTEFED IKSGYRIDFY FDENPYFENK VLSKEFHLNE SGDPSSKSTE IKWKSGKDLT 190 200 210 220 230 240 KRSSQTQNKA SRKRQHEEPE SFFTWFTDHS DAGADELGEV IKDDIWPNPL QYYLVPDMDD 250 260 270 280 290 EEGEGEEDDD DDEEEEGLED IDEEGDEDEG EEDEDDDEGE EGEEDEGEDD « Hide
Isoform 2 (TAF-I beta) [UniParc]. Checksum: 52A6F516686010CE Show »		277	32,103
10 20 30 40 50 60 MSAPAAKVSK KELNSNHDGA DETSEKEQQE AIEHIDEVQN EIDRLNEQAS EEILKVEQKY 70 80 90 100 110 120 NKLRQPFFQK RSELIAKIPN FWVTTFVNHP QVSALLGEED EEALHYLTRV EVTEFEDIKS 130 140 150 160 170 180 GYRIDFYFDE NPYFENKVLS KEFHLNESGD PSSKSTEIKW KSGKDLTKRS SQTQNKASRK 190 200 210 220 230 240 RQHEEPESFF TWFTDHSDAG ADELGEVIKD DIWPNPLQYY LVPDMDDEEG EGEEDDDDDE 250 260 270 EEEGLEDIDE EGDEDEGEED EDDDEGEEGE EDEGEDD « Hide

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3' half to different genes: characterization of the set gene." von Lindern M., van Baal S., Wiegant J., Raap A., Hagemeijer A., Grosveld G. Mol. Cell. Biol. 12:3346-3355(1992) [PubMed: 1630450] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[2]	"Purification and characterization of two putative HLA class II associated proteins: PHAPI and PHAPII." Vaesen M., Barnikol-Watanabe S., Goetz H., Adil Awni L., Cole T., Zimmermann B., Kratzin H.D., Hilschmann N. Biol. Chem. Hoppe-Seyler 375:113-126(1994) [PubMed: 8192856] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PARTIAL PROTEIN SEQUENCE.
[3]	"Replication factor encoded by a putative oncogene, set, associated with myeloid leukemogenesis." Nagata K., Kawase H., Handa H., Yano K., Yamasaki M., Ishimi Y., Okuda A., Kikuchi A., Matsumoto K. Proc. Natl. Acad. Sci. U.S.A. 92:4279-4283(1995) [PubMed: 7753797] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PROTEIN SEQUENCE OF 14-35; 40-60; 75-90 AND 155-167, ACTIVATION OF DNA REPLICATION. Tissue: Cervix carcinoma.
[4]	"The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A." Li M., Makkinje A., Damuni Z. J. Biol. Chem. 271:11059-11062(1996) [PubMed: 8626647] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Kidney.
[5]	"Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau." Tsujio I., Zaidi T., Xu J., Kotula L., Grundke-Iqbal I., Iqbal K. FEBS Lett. 579:363-372(2005) [PubMed: 15642345] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Brain.
[6]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[7]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain.
[8]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. Dunham I. Nature 429:369-374(2004) [PubMed: 15164053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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] (ISOFORM 2). Tissue: Testis.
[10]	"Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia." Adachi Y., Pavlaki G.N., Copeland T.D. J. Biol. Chem. 269:2258-2262(1994) [PubMed: 8294483] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, CHARACTERIZATION.
[11]	"A relative factor in human rectum carcinoma." Wang L.C., Chen Y. Submitted (APR-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-241 (ISOFORM 2).
[12]	"Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor." Carlson S.G., Eng E., Kim E.-G., Perlman E.J., Copeland T.D., Ballermann B.J. J. Am. Soc. Nephrol. 9:1873-1880(1998) [PubMed: 9773788] [Abstract] Cited for: EXPRESSION IN THE KIDNEY.
[13]	"Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the Set oncoprotein." Seo S.-B., McNamara P., Heo S., Turner A., Lane W.S., Chakravarti D. Cell 104:119-130(2001) [PubMed: 11163245] [Abstract] Cited for: INHIBITION OF HISTONE ACETYLATION.
[14]	"Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET." Minakuchi M., Kakazu N., Gorrin-Rivas M.J., Abe T., Copeland T.D., Ueda K., Adachi Y. Eur. J. Biochem. 268:1340-1351(2001) [PubMed: 11231286] [Abstract] Cited for: INTERACTION WITH SETBP1. Tissue: Cervix carcinoma.
[15]	"HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A." Fan Z., Beresford P.J., Zhang D., Lieberman J. Mol. Cell. Biol. 22:2810-2820(2002) [PubMed: 11909973] [Abstract] Cited for: INTERACTION WITH HMGB2.
[16]	"Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor." Fan Z., Beresford P.J., Oh D.Y., Zhang D., Lieberman J. Cell 112:659-672(2003) [PubMed: 12628186] [Abstract] Cited for: NME1 INHIBITION, SUBCELLULAR LOCATION, DESCRIPTION OF THE SET COMPLEX.
[17]	Erratum Fan Z., Beresford P.J., Oh D.Y., Zhang D., Lieberman J. Cell 115:241-241(2003)
[18]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7 (ISOFORM 1) AND SER-15 (ISOFORM 2), MASS SPECTROMETRY. Tissue: Epithelium.
[19]	"Substrate and functional diversity of lysine acetylation revealed by a proteomics survey." Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T., Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y. Mol. Cell 23:607-618(2006) [PubMed: 16916647] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-11 (ISOFORM 2), MASS SPECTROMETRY. Tissue: Epithelium.
[20]	"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-7, MASS SPECTROMETRY. Tissue: Epithelium.
[21]	"Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry." Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A. Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007) [PubMed: 17287340] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-23 (ISOFORM 2), MASS SPECTROMETRY.
[22]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, MASS SPECTROMETRY.
[23]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, MASS SPECTROMETRY.
+	Additional computationally mapped references.