| Structural highlights
Function
HEXI1_HUMAN Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor. In cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation. May also regulate NF-kappa-B, ESR1, NR3C1 and CIITA-dependent transcriptional activity.[1] [2] [3] [4] [5] [6] [7] [8] [9]
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
Hexim1 is a cellular protein that associates with the positive transcription elongation factor b (P-TEFb) to regulate RNA polymerase II elongation of nascent mRNA transcripts. It directly binds to Cyclin T1 of P-TEFb and inhibits the kinase activity of Cdk9, leading to an arrest of transcription elongation. Here, we report the solution structure of the Cyclin T binding domain (TBD) of Hexim1 that forms a parallel coiled-coil homodimer composed of two segments and a preceding alpha helix that folds back onto the first coiled-coil unit. NMR titration, fluorescence, and immunoprecipitation experiments revealed the binding interface to Cyclin T1, which covers a large surface on the first coiled-coil segment. Electrostatic interactions between an acidic patch on Hexim1 and positively charged residues of Cyclin T1 drive the complex formation that is confirmed by mutagenesis data on Hexim1 mediated transcription regulation in cells. Thus, our studies provide structural insights how Hexim1 recognizes the Cyclin T1 subunit of P-TEFb, which is a key step toward the regulation of transcription elongation.
Structure of the Cyclin T binding domain of Hexim1 and molecular basis for its recognition of P-TEFb.,Dames SA, Schonichen A, Schulte A, Barboric M, Peterlin BM, Grzesiek S, Geyer M Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14312-7. Epub 2007 Aug 27. PMID:17724342[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wittmann BM, Wang N, Montano MM. Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors. Cancer Res. 2003 Aug 15;63(16):5151-8. PMID:12941847
- ↑ Ouchida R, Kusuhara M, Shimizu N, Hisada T, Makino Y, Morimoto C, Handa H, Ohsuzu F, Tanaka H. Suppression of NF-kappaB-dependent gene expression by a hexamethylene bisacetamide-inducible protein HEXIM1 in human vascular smooth muscle cells. Genes Cells. 2003 Feb;8(2):95-107. PMID:12581153
- ↑ Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol Cell. 2003 Oct;12(4):971-82. PMID:14580347
- ↑ Michels AA, Nguyen VT, Fraldi A, Labas V, Edwards M, Bonnet F, Lania L, Bensaude O. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003 Jul;23(14):4859-69. PMID:12832472
- ↑ Michels AA, Fraldi A, Li Q, Adamson TE, Bonnet F, Nguyen VT, Sedore SC, Price JP, Price DH, Lania L, Bensaude O. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. EMBO J. 2004 Jul 7;23(13):2608-19. Epub 2004 Jun 17. PMID:15201869 doi:http://dx.doi.org/10.1038/sj.emboj.7600275
- ↑ Yik JH, Chen R, Pezda AC, Zhou Q. Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription. J Biol Chem. 2005 Apr 22;280(16):16368-76. Epub 2005 Feb 14. PMID:15713661 doi:http://dx.doi.org/M500912200
- ↑ Wittmann BM, Fujinaga K, Deng H, Ogba N, Montano MM. The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1. Oncogene. 2005 Aug 25;24(36):5576-88. PMID:15940264 doi:http://dx.doi.org/1208728
- ↑ Shimizu N, Ouchida R, Yoshikawa N, Hisada T, Watanabe H, Okamoto K, Kusuhara M, Handa H, Morimoto C, Tanaka H. HEXIM1 forms a transcriptionally abortive complex with glucocorticoid receptor without involving 7SK RNA and positive transcription elongation factor b. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8555-60. Epub 2005 Jun 7. PMID:15941832 doi:http://dx.doi.org/0409863102
- ↑ Kohoutek J, Blazek D, Peterlin BM. Hexim1 sequesters positive transcription elongation factor b from the class II transactivator on MHC class II promoters. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17349-54. Epub 2006 Nov 6. PMID:17088550 doi:http://dx.doi.org/0603079103
- ↑ Dames SA, Schonichen A, Schulte A, Barboric M, Peterlin BM, Grzesiek S, Geyer M. Structure of the Cyclin T binding domain of Hexim1 and molecular basis for its recognition of P-TEFb. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14312-7. Epub 2007 Aug 27. PMID:17724342
|
