Structural analyses of CREB-CBP transcriptional activator-coactivator complexes by NMR spectroscopy: Implications for mapping the boundaries of structural domains

Ishwar Radhakrishnan, Gabriela C. Pérez-Alvarado, David Parker, H. Jane Dyson, Marc R. Montminy, Peter E. Wright*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

A number of signal-dependent and development-specific transcription factors recruit CREB binding protein (CBP) for their transactivation function. The KIX domain of CBP is a common docking site for many of these transcription factors. We recently determined the solution structure of the KIX domain complexed to one of its targets, the Ser133-phosphorylated kinase inducible transactivation domain (pKID) of the cyclic AMP response element binding protein. The NMR studies have now been extended to a slightly longer KIX construct that, unlike the original KIX construct, is readily amenable to structural analysis in both the free and pKID-bound forms. This addition of six residues (KRRSRL) to the C terminus of the original construct elongates the C-terminal α3 helix of KIX by about eight residues. On the basis of the NMR structure of the original KIX construct, residues in the extended helix are predicted to be solvent exposed and thus are not expected to contribute to the hydrophobic core of the domain. Their role appears to be in the stabilization of the α3 helix through favorable electrostatic interactions with the helix dipole, which in turn confers stability on the core of the KIX domain. These results have important implications for the identification of novel protein domain boundaries. Chemical shift perturbation mapping firmly establishes a similar mode of pKID binding to the longer KIX construct and rules out any additional intermolecular interactions between residues in the C-terminal extension and pKID.

Original languageEnglish (US)
Pages (from-to)859-865
Number of pages7
JournalJournal of Molecular Biology
Volume287
Issue number5
DOIs
StatePublished - Apr 16 1999

Keywords

  • CBP
  • CREB
  • Domain mapping
  • NMR spectroscopy
  • Protein-protein interactions

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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