Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

Qianyi Luo, Kristin Viste, Janny Concha Urday-Zaa, Ganesan Senthil Kumar, Wen Wei Tsai, Afsaneh Talai, Kelly E. Mayo, Marc Montminy, Ishwar Radhakrishnan

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Basic leucine zipper (bZip) transcription factors regulate cellular gene expression in response to a variety of extracellular signals and nutrient cues. Although the bZip domain is widely known to play significant roles in DNA binding and dimerization, recent studies point to an additional role for this motif in the recruitment of the transcriptional apparatus. For example, the cAMP response element binding protein (CREB)-regulated transcriptional coactivator (CRTC) family of transcriptional coactivators has been proposed to promote the expression of calcium and cAMP responsive genes, by binding to the CREB bZip in response to extracellular signals. Here we show that the CREB-binding domain (CBD) of CRTC2 folds into a single isolated 28-residue helix that seems to be critical for its interaction with the CREB bZip. The interaction is of micromolar affinity on palindromic and variant half-site cAMP response elements (CREs). The CBD and CREB assemble on the CRE with 2:2:1 stoichiometry, consistent with the presence of one CRTC binding site on each CREB monomer. Indeed, the CBD helix and the solvent-exposed residues in the dimeric CREB bZip coiled-coil form an extended protein- protein interface. Because mutation of relevant bZip residues in this interface disrupts the CRTC interaction without affecting DNA binding, our results illustrate that distinct DNA binding and transactivation functions are encoded within the structural constraints of a canonical bZip domain.

Original languageEnglish (US)
Pages (from-to)20865-20870
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number51
DOIs
StatePublished - Dec 18 2012
Externally publishedYes

Keywords

  • Cellular signaling
  • Protein-protein interaction
  • Transcription regulation

ASJC Scopus subject areas

  • General

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