Phosphorylation-induced transient intrinsic structure in the kinase-inducible domain of CREB facilitates its recognition by the KIX domain of CBP

Iván Solt, Csaba Magyar, István Simon, Peter Tompa, Monika Fuxreiter

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Phosphorylation at Ser-133 of the kinase inducible domain of CREB (KID) triggers its binding to the KIX domain of CBP via a concomitant coil-to-helix transition. The exact role of this key event is still puzzling: it does not switch between disordered and ordered states, nor its direct interactions fully account for selectivity. Hence, we reasoned that phosphorylation may shift the conformational preferences of KID towards a binding-competent state. To this end we investigated the intrinsic structural properties of the unbound KID in phosphorylated and unphosphorylated forms by simulated annealing and molecular dynamics simulations. Although helical populations show subtle differences, phosphorylation reduces the flexibility of the turn segment connecting the two helices in the complexed structure and induces a transient structural element that corresponds to its bound conformation. It is stabilized by the pSer-133-Arg-131 interaction, which is absent from the unphosphorylated KID. Diminishing this coupling decreases the 3.1 kcal/mol contribution of pSer-133 to the binding free energy (ΔGbind) of the phosphorylated KID to KIX by 1.1 kcal/mol, as computed in reference to Ser-133. In a binding competent form of the S133E KID mutant, the contribution of Glu-133 to ΔG bind is by 1.5 kcal/mol smaller than that of pSer, suggesting that altered structural properties due to pSer → Glu replacement impair the binding affinity. Thus, we propose that phoshorylation contributes to selectivity not merely by the direct interactions of the phosphate group with KIX, but also by promoting the formation of a transient structural element in the highly conserved turn segment.

Original languageEnglish
Pages (from-to)749-757
Number of pages9
JournalProteins: Structure, Function and Genetics
Volume64
Issue number3
DOIs
Publication statusPublished - Aug 15 2006

Keywords

  • Disorder-to-order transition
  • Induced folding
  • Molecular recognition
  • Natively unfolded protein
  • Preformed structural element
  • Structural stability

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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