PDBsum entry 1kbh

Transcription

PDB id: 1kbh

Contents

Protein chains

47 a.a. *

59 a.a. *

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Mutual synergistic folding in recruitment of cbp/p300 by p160 nuclear receptor coactivators.

Authors

S.J.Demarest, M.Martinez-Yamout, J.Chung, H.Chen, W.Xu, H.J.Dyson, R.M.Evans, P.E.Wright.

Ref.

Nature, 2002, 415, 549-553. [DOI no: 10.1038/415549a]

PubMed id

11823864

Abstract

Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of genes that are essential for development, reproduction and homeostasis. The hormone response is mediated through recruitment of p160 receptor coactivators and the general transcriptional coactivator CBP/p300, which function synergistically to activate transcription. These coactivators exhibit intrinsic histone acetyltransferase activity, function in the remodelling of chromatin, and facilitate the recruitment of RNA polymerase II and the basal transcription machinery. The activities of the p160 coactivators are dependent on CBP. Both coactivators are essential for proper cell-cycle control, differentiation and apoptosis, and are implicated in cancer and other diseases. To elucidate the molecular basis of assembling the multiprotein activation complex, we undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors. Here we show that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. Our study uncovers a unique mechanism, called 'synergistic folding', through which p160 coactivators recruit CBP/p300 to allow transmission of the hormonal signal to the transcriptional machinery.

Figure 2.
Figure 2: Solution structure of the ACTR -CBP complex. ACTR is pink and CBP blue in all figures. a, Stereo view showing best-fit superposition of backbone heavy atoms within the structured region. Residues at the boundaries of the structured region are numbered. b, Ribbon representation, in the same orientation as a. Helices A 1 -3 and C 1 -3, and the polyglutamine (polyQ) stretch in CBP are labelled. c, Surface representation of CBP domain, showing the hydrophobic groove formed by C 1 and C 3 that accommodates helix A 1 of ACTR. The orientation is the same as in a and b. Bulky hydrophobic residues from A 1 embedded within the groove are labelled. d, Surface representation of CBP domain, rotated to show the hydrophobic cleft that binds helix A 2 of ACTR. The interactions between A 3 and C 3 are also shown. Bulky hydrophobic residues of ACTR that form the molecular interface are labelled, as is Asp 1068, which participates in the buried salt bridge.

Figure 3.
Figure 3: Conserved interactions in the ACTR -CBP complex. a, Sequence alignment of the CBP binding domain of human ACTR(1018 -1088) and a representative set of p160 coactivators. b, Sequence alignment of the ACTR binding domain of murine CBP with other members of the CBP/p300 family. Conserved hydrophobic residues (green), conserved acidic residues (red), conserved basic residues (blue), and other conserved residues (orange) are indicated (h, human; m, murine, x, Xenopus laevis; d, Drosophila; dr, Danio rerio; c, Caenorhabditis elegans). c, -X-X- - and - -X-X- hydrophobic contact map defining the interface between ACTR and CBP ( denotes hydrophobic residue). The four -X-X- - motifs that comprise the hydrophobic core are enclosed by a green box. The buried intermolecular salt bridge is indicated. d, Close-up of the salt bridge between Arg 2105 and Asp 1068 salt bridge. The solvent-accessible surface of ACTR is shown.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2002, 415, 549-553) copyright 2002.