| Structural highlights
2agh is a 3 chain structure with sequence from Human and Lk3 transgenic mice. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | Myb (LK3 transgenic mice), CBP, CREBBP (LK3 transgenic mice), MLL, ALL1, HRX, HTRX, TRX1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Disease
[MLL1_HUMAN] Defects in MLL are the cause of Wiedemann-Steiner syndrome (WDSTS) [MIM:605130]. A syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature. Facial characteristics include long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures.[1] [2] Note=Chromosomal aberrations involving MLL are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins MLL-MLLT1, MLL-MLLT3 and MLL-ELL interact with PPP1R15A and, on the contrary to unfused MLL, inhibit PPP1R15A-induced apoptosis.[3] Note=A chromosomal aberration involving MLL may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.[4]
Function
[MYB_MOUSE] Transcriptional activator; DNA-binding protein that specifically recognize the sequence 5'-YAAC[GT]G-3'. Plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells. [MLL1_HUMAN] Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.[5] [6] [7] [8] [CBP_MOUSE] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300 (By similarity).[9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Regulation of transcription requires interactions between transcriptional activators and transcriptional co-activator CREB binding protein (CBP). The KIX domain of CBP can bind simultaneously to two different proteins, providing an additional mechanism for transcriptional regulation. Here we describe the solution structure of the ternary complex formed by cooperative binding of activation domains from the c-Myb and mixed lineage leukemia (MLL) transcription factors to the KIX domain. The MLL and c-Myb domains form helices that bind to two distinct hydrophobic grooves on opposite faces of KIX. Compared to the binary KIX:c-Myb complex, significant changes are observed in the structure of KIX at the MLL binding interface in the ternary complex. Two regions of KIX that are disordered in the binary complex become structured in the ternary complex: a flexible loop forms intimate contacts with bound MLL, and the C-terminal helix is extended and stabilized by MLL binding. This structural change results in the formation of additional electrostatic/polar interactions between KIX and the bound c-Myb, providing a structural basis for the cooperativity observed for the ternary complex.
Structural basis for cooperative transcription factor binding to the CBP coactivator.,De Guzman RN, Goto NK, Dyson HJ, Wright PE J Mol Biol. 2006 Feb 3;355(5):1005-13. Epub 2005 Oct 5. PMID:16253272[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ Jr, Tkachuk DC. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999 Oct;19(10):7050-60. PMID:10490642
- ↑ Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet. 2012 Aug 10;91(2):358-64. doi: 10.1016/j.ajhg.2012.06.008. Epub, 2012 Jul 12. PMID:22795537 doi:10.1016/j.ajhg.2012.06.008
- ↑ Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ Jr, Tkachuk DC. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999 Oct;19(10):7050-60. PMID:10490642
- ↑ Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ Jr, Tkachuk DC. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999 Oct;19(10):7050-60. PMID:10490642
- ↑ Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ Jr, Tkachuk DC. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999 Oct;19(10):7050-60. PMID:10490642
- ↑ Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, Dubois G, Mazo A, Croce CM, Canaani E. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002 Nov;10(5):1119-28. PMID:12453419
- ↑ Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL, Roeder RG. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005 Jun 17;121(6):873-85. PMID:15960975 doi:10.1016/j.cell.2005.04.031
- ↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
- ↑ Hung HL, Lau J, Kim AY, Weiss MJ, Blobel GA. CREB-Binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol. 1999 May;19(5):3496-505. PMID:10207073
- ↑ Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8. PMID:11701890 doi:10.1126/science.1065961
- ↑ Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25. PMID:15220471 doi:10.1073/pnas.0400593101
- ↑ Kuo HY, Chang CC, Jeng JC, Hu HM, Lin DY, Maul GG, Kwok RP, Shih HM. SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):16973-8. Epub 2005 Nov 15. PMID:16287980 doi:10.1073/pnas.0504460102
- ↑ De Guzman RN, Goto NK, Dyson HJ, Wright PE. Structural basis for cooperative transcription factor binding to the CBP coactivator. J Mol Biol. 2006 Feb 3;355(5):1005-13. Epub 2005 Oct 5. PMID:16253272 doi:http://dx.doi.org/10.1016/j.jmb.2005.09.059
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