Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery.
Eukaryotic transcriptional repressors function by recruiting large coregulatory complexes that target histone deacetylase enzymes to gene promoters and enhancers. Transcriptional repression complexes, assembled by the corepressor NCoR and its homolog SMRT, are crucial in many processes, including development and metabolic physiology. The core repression complex involves the recruitment of three proteins, HDAC3, GPS2 and TBL1, to a highly conserved repression domain within SMRT and NCoR. We have used structural and functional approaches to gain insight into the architecture and biological role of this complex. We report the crystal structure of the tetrameric oligomerization domain of TBL1, which interacts with both SMRT and GPS2, and the NMR structure of the interface complex between GPS2 and SMRT. These structures, together with computational docking, mutagenesis and functional assays, reveal the assembly mechanism and stoichiometry of the corepressor complex.
Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Leicester, UK.
Jasmeen
J
Oberoi
Louise
L
Fairall
Peter J
PJ
Watson
Ji-Chun
JC
Yang
Zsolt
Z
Czimmerer
Thorsten
T
Kampmann
Benjamin T
BT
Goult
Jacquie A
JA
Greenwood
John T
JT
Gooch
Bettina C
BC
Kallenberger
Laszlo
L
Nagy
David
D
Neuhaus
John W R
JW
Schwabe
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D056985:Nuclear Receptor Co-Repressor 2 / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015293:Transducin / Q000737:chemistry* / Q000378:metabolism
C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; C485613:Tbl1x protein, mouse; D015293:Transducin
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