PMID:11959977
| Citation |
Dames, SA, Martinez-Yamout, M, De Guzman, RN, Dyson, HJ and Wright, PE (2002) Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. Proc. Natl. Acad. Sci. U.S.A. 99:5271-6 |
|---|---|
| Abstract |
The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates transcription of critical adaptive genes by recruitment of the general coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha). Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of tumor growth. To delineate the structural basis for this interaction, we have determined the solution structure of the complex between the carboxy-terminal activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of cyclic-AMP response element binding protein (CREB) binding protein (CBP). Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part of the CH3) domain of CBP, differences occur in the packing of helices that can account for differences in specificity. The unbound CAD is intrinsically disordered and remains relatively extended upon binding, wrapping almost entirely around the TAZ1 domain in a groove through much of its surface. Three short helices are formed upon binding, stabilized by intermolecular interactions. The Asn-803 side chain, which functions as a hypoxic switch, is located on the second of these helices and is buried in the molecular interface. The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in TAZ1, providing extensive intermolecular hydrophobic interactions that contribute to the stability of the complex. The structure of this complex provides new insights into the mechanism through which Hif-1 alpha recruits CBP/p300 in response to hypoxia. |
| Links |
PubMed PMC122759 Online version:10.1073/pnas.082121399 |
| Keywords |
Amino Acid Motifs; Amino Acid Sequence; Animals; Anoxia; Binding Sites; Cyclic AMP/metabolism; E1A-Associated p300 Protein; Hydrogen Bonding; Hypoxia-Inducible Factor 1, alpha Subunit; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Sequence Data; Nuclear Proteins/chemistry; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Trans-Activators/chemistry; Transcription Factors/chemistry; Transcription, Genetic; Two-Hybrid System Techniques; Zinc/chemistry |
| edit table |
Significance
You can help EcoliWiki by summarizing why this paper is useful
Useful Materials and Methods
You can help Ecoliwiki by describing the useful materials (strains, plasmids, antibodies, etc) described in this paper.
Annotations
<annotationlinks/>
EcoliWiki Links
Add links to pages that link here (e.g. gene, product, method pages)
References
See Help:References for how to manage references in EcoliWiki.