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.

Abstract

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.

• Authors: Roberto N De Guzman, Maria A Martinez-Yamout, H Jane Dyson, Peter E Wright
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 4 Pg. 3042-9 (Jan 23 2004) ISSN: 0021-9258 [Print] United States
• PMID: 14594809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CITED2 protein, human
• Cited2 protein, mouse
• DNA-Binding Proteins
• HIF1A protein, human
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ligands
• Nuclear Proteins
• Repressor Proteins
• Trans-Activators
• Transcription Factors
• CREB-Binding Protein
• CREBBP protein, human
• Crebbp protein, mouse

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• CREB-Binding Protein
• DNA-Binding Proteins (chemistry, metabolism)
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ligands
• Mice
• Models, Molecular
• Molecular Sequence Data
• Nuclear Proteins (chemistry, metabolism)
• Protein Binding
• Protein Conformation
• Protein Structure, Tertiary
• Repressor Proteins (chemistry, metabolism)
• Sequence Alignment
• Trans-Activators (chemistry, metabolism)
• Transcription Factors