| 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]
Publication Abstract from PubMed
The positive transcription elongation factor P-TEFb mediates the transition from transcription initiation to productive elongation by phosphorylation of the C-terminal domain of RNA polymerase II. P-TEFb is negatively regulated by the cellular protein Hexim1 (hexamethylene bisacetamide-inducible protein 1), which is highly conserved in higher eukaryotes. The C-terminal coiled-coil domain of Hexim1 recognizes the Cyclin T subunit of P-TEFb, whereas a central PYNT motif is required to inhibit the cyclin-dependent kinase Cdk9 by a yet unknown mechanism. Here, the crystal structure of the Cyclin-T-binding domain (TBD) of human Hexim1 was determined at 2.1 A resolution using a deletion mutant of three residues in its central stammer motif. The structure showed a continuous parallel coiled-coil domain of nine hepta-repeats with a preceding helix encompassing up to 15 residues. Two uncommon residues at heptad a positions in the N-terminal part of the coiled-coil structure, Lys284 and Tyr291, stabilize the preceding helix by a tight intermolecular hydrogen bond network with residues of the opposing chain. These interactions delineate a characteristic turn between both helices that is supposed to mediate binding to Cyclin T1. Stabilization of the coiled-coil domain by deletion of the stammer region was confirmed by NMR spectroscopic and backbone dynamic analyses analyzing wild-type TBD and three mutant variants. This study thus provides structural insights into the recognition of the regulator protein Hexim1 by P-TEFb and the modulation of coiled-coil dynamics by specific discontinuities.
Structure and Dynamics of a Stabilized Coiled-Coil Domain in the P-TEFb Regulator Hexim1.,Bigalke JM, Dames SA, Blankenfeldt W, Grzesiek S, Geyer M J Mol Biol. 2011 Oct 18. PMID:22033481[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
- ↑ Bigalke JM, Dames SA, Blankenfeldt W, Grzesiek S, Geyer M. Structure and Dynamics of a Stabilized Coiled-Coil Domain in the P-TEFb Regulator Hexim1. J Mol Biol. 2011 Oct 18. PMID:22033481 doi:10.1016/j.jmb.2011.10.022
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