1r8u

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Revision as of 16:55, 12 November 2007

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NMR structure of CBP TAZ1/CITED2 complex

Overview

The TAZ1 domain of the homologous transcriptional coactivators, CREB-binding protein (CBP) and p300 forms a complex with CITED2, (CBP/p300-interacting transactivator with ED-rich tail), inhibiting the, activity of the hypoxia inducible factor (HIF-1alpha) and thereby, attenuating the cellular response to low tissue oxygen concentration. We, report the NMR structure of the CBP TAZ1 domain bound to the activation, domain of CIT-ED2. The structure of TAZ1, consisting of four alpha-helices, (alpha(1)-alpha(4)) stabilized by three zinc atoms, is very similar in the, CITED2 and HIF-1alpha complexes. The activation domain of CITED2 is, unstructured when free and folds upon binding, forming a helix (termed, alpha(A)) and an extended structure that wraps around TAZ1. The CITED2, alpha(A) helix packs in the TAZ1 alpha(1)/alpha(4) interface, a site that, forms weak interactions with the poorly defined aminoterminal alpha-helix, of HIF-1alpha. CITED2 and HIF-1alpha both contain a four residue motif, LP(E/Q)L, which binds in the TAZ1 alpha(1)/alpha(2)/alpha(3) junction in, each complex. The carboxyl-terminal region of CITED2 forms an extended, structure with hydrophobic contacts in the TAZ1 alpha(1)/alpha(3), interface in the site occupied by the HIF-1alpha alpha(B) helix. CITED2, does not bind at all to the TAZ1 site occupied by the HIF-1alpha, carboxyl-terminal helix. The HIF-1alpha and CITED2 domains utilize partly, overlapping surfaces of TAZ1 to achieve high affinity binding and to, compete effectively with each other for interaction with CBP/p300; CITED2, and HIF-1alpha use these binding sites differently to maintain similar, binding affinities in order to displace each other in a feedback loop, during the hypoxic response.

About this Structure

1R8U is a Protein complex structure of sequences from Homo sapiens and Mus musculus with ZN as ligand. Full crystallographic information is available from OCA.

Reference

Interaction of the TAZ1 domain of the CREB-binding protein with the activation domain of CITED2: regulation by competition between intrinsically unstructured ligands for non-identical binding sites., De Guzman RN, Martinez-Yamout MA, Dyson HJ, Wright PE, J Biol Chem. 2004 Jan 23;279(4):3042-9. Epub 2003 Oct 31. PMID:14594809

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