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Role of Secondary Structure in Discrimination between Constitutive and Inducible Activators

机译：二级结构在本构激活剂和诱导激活剂之间的区分中的作用

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摘要

We have examined structural differences between the proto-oncogene c-Myb and the cyclic AMP-responsive factor CREB that underlie their constitutive or signal-dependent activation properties. Both proteins stimulate gene expression via activating regions that articulate with a shallow hydrophobic groove in the KIX domain of the coactivator CREB-binding protein (CBP). Three hydrophobic residues in c-Myb that are conserved in CREB function importantly in cellular gene activation and in complex formation with KIX. These hydrophobic residues are assembled on one face of an amphipathic helix in both proteins, and mutations that disrupt c-Myb or CREB helicity in this region block interaction of either factor with KIX. Binding of the helical c-Myb domain to KIX is accompanied by a substantial increase in entropy that compensates for the comparatively low enthalpy of complex formation. By contrast, binding of CREB to KIX entails a large entropy cost due to a random coil-to-helix transition in CREB that accompanies complex formation. These results indicate that the constitutive and inducible activation properties of c-Myb and CREB reflect secondary structural characteristics of their corresponding activating regions that influence the thermodynamics of formation of a complex with CBP.
机译：我们已经检查了原癌基因c-Myb和环状AMP反应因子CREB之间的结构差异，这些差异构成了它们的组成型或信号依赖性激活特性。两种蛋白都通过激活区刺激基因表达，该激活区与辅助激活剂CREB结合蛋白（CBP）的KIX域中的浅疏水沟相连。 CREB中保守的c-Myb中的三个疏水残基在细胞基因激活和与KIX的复合物形成中起重要作用。这些疏水残基在两种蛋白的两亲性螺旋的一个面上组装，并且破坏该区域中c-Myb或CREB螺旋的突变会阻止任一因子与KIX的相互作用。螺旋c-Myb结构域与KIX的结合伴随着熵的大幅增加，从而补偿了复合物形成的相对较低的焓。相比之下，CREB与KIX的结合需要很大的熵代价，这是由于CREB中伴随复杂形成的随机线圈到螺旋过渡。这些结果表明，c-Myb和CREB的本构和诱导激活特性反映了其相应激活区域的二级结构特征，这些特征影响了CBP配合物形成的热力学。

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