CREB的激酶可诱导结构域中的磷酸化诱导的瞬时内在结构促进了CBP的KIX结构域对其的识别。,Proteins: Structure, Function, and Bioinformatics

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CREB的激酶可诱导结构域中的磷酸化诱导的瞬时内在结构促进了CBP的KIX结构域对其的识别。
Proteins: Structure, Function, and Bioinformatics ( IF 3.2 ) Pub Date : 2006-06-09 , DOI: 10.1002/prot.21032
Iván Solt ₁ , Csaba Magyar , István Simon , Peter Tompa , Monika Fuxreiter

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CREB激酶诱导结构域（KID）的Ser-133处的磷酸化通过伴随的从线圈到螺旋的转变触发其与CBP的KIX结构域的结合。这个关键事件的确切作用仍然令人费解：它不会在无序状态和有序状态之间切换，也不会直接相互作用来充分说明选择性。因此，我们认为磷酸化可能会使KID的构象偏爱向结合态迁移。为此，我们通过模拟退火和分子动力学模拟研究了磷酸化和非磷酸化形式的未结合KID的固有结构性质。尽管螺旋种群显示出细微的差异，磷酸化降低了在复杂结构中连接两个螺旋的转向链段的柔性，并诱导了与其结合构象相对应的瞬时结构元件。它通过未磷酸化的KID中不存在的pSer-133-Arg-131相互作用得以稳定。如参考Ser-133所计算的，减少这种偶联将pSer-133对磷酸化的KID与KIX的结合自由能（DeltaGbind）的3.1kcal / mol的贡献降低了1.1kcal / mol。在S133E KID突变体的结合感受态形式中，Glu-133对DeltaGbind的贡献比pSer小1.5 kcal / mol，这表明由于pSer-> Glu替代引起的结构特性改变会削弱结合亲和力。从而，

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

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 (DeltaGbind) 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 DeltaGbind 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.

更新日期：2019-11-01

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