Journal of Biological Chemistry
Volume 279, Issue 4, 23 January 2004, Pages 3042-3049
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Protein Structure and Folding
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*

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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-1α) 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 α-helices (α14) stabilized by three zinc atoms, is very similar in the CITED2 and HIF-1α complexes. The activation domain of CITED2 is unstructured when free and folds upon binding, forming a helix (termed αA) and an extended structure that wraps around TAZ1. The CITED2 αA helix packs in the TAZ1 α14 interface, a site that forms weak interactions with the poorly defined aminoterminal α-helix of HIF-1α. CITED2 and HIF-1α both contain a four residue motif, LP(E/Q)L, which binds in the TAZ1 α123 junction in each complex. The carboxyl-terminal region of CITED2 forms an extended structure with hydrophobic contacts in the TAZ1 α13 interface in the site occupied by the HIF-1α αB helix. CITED2 does not bind at all to the TAZ1 site occupied by the HIF-1α carboxyl-terminal helix. The HIF-1α 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-1α use these binding sites differently to maintain similar binding affinities in order to displace each other in a feedback loop during the hypoxic response.

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The assigned chemical shift list has been deposited in the BioMagRes-Bank with accession number 5987.

The atomic coordinates and structure factors (code 1R8U) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

*

This work was supported by National Institutes of Health Grant CA96865. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a postdoctoral fellowship from the Leukemia and Lymphoma Society.