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首页> 外文期刊>Biochemistry >Functional Consequences of Preorganized Helical Structure in the Intrinsically Disordered Cell-Cycle Inhibitor p27~(Kipl)
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Functional Consequences of Preorganized Helical Structure in the Intrinsically Disordered Cell-Cycle Inhibitor p27~(Kipl)

机译：固有紊乱的细胞周期抑制剂p27〜（Kipl）中预组织的螺旋结构的功能后果。

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摘要

p27~(Kipl) contributes to cell-cycle regulation by inhibiting cyclin-dependent kinase (Cdk) activity. The p27 Cdk-inhibition domain has an ordered conformation comprising an #alpha#-helix, a 3_(10) helix, and #beta#-structure when bound to cyclin A-Cdk2. In contrast, the unbound p27 Cdk-inhibition domain is intrinsically disordered (natively unfolded) as shown by circular dichroism spectroscopy, lack of chemical-shift dispersion, and negative heteronuclear nuclear Overhauser effects. The intrinsic disorder is not due to the excision of the Cdk-inhibition domain from p27, since circular dichroism spectra of the full-length protein are also indicative of a largely unfloded protein. Both the inhibition domain and full-length p27 are active as cyclin A-Cdk2 inhibitors. Using circular dichroism and proline mutagenesis, we demonstrate that the unbound p27 Cdk-inhibition domain is not completely unfolded. the domain contains marginally stable helical structure that presages the #alpha#-helix, but not the 3_(10) helix, adopted upon binding cyclic A-Cdk2. Increasing or reducing the stability of the particlly preformed #alpha#-helix in the isolated p27 domain with alanine or proine substitutions did not affect formation fo the p27-inhibited cyclic A-Cdk2 complex in energetic terms. However, stabilizatio of the helix with alanine hindered kinetically the formation of the inhibited complex, suggesting that p27 derives a kinetic advantage from intrinsic structural disorder.
机译：p27〜（Kipl）通过抑制细胞周期蛋白依赖性激酶（Cdk）的活性来促进细胞周期的调控。当与细胞周期蛋白A-Cdk2结合时，p27 Cdk抑制域具有包含＃alpha＃-螺旋，3_（10）螺旋和＃beta＃-结构的有序构象。相比之下，未结合的p27 Cdk抑制域本质上是无序的（自然展开），如圆二色性光谱，缺乏化学位移分散性和异核核Overhauser效应所致。内在的疾病不是由于从p27切除了Cdk抑制域，因为全长蛋白质的圆二色性光谱也表明了大量未修饰的蛋白质。抑制域和全长p27均作为细胞周期蛋白A-Cdk2抑制剂具有活性。使用圆二色性和脯氨酸诱变，我们证明未绑定的p27 Cdk抑制域并不完全展开。该结构域包含边缘稳定的螺旋结构，该结构预示结合环A-Cdk2时采用的＃alpha＃-螺旋，而不是3_（10）螺旋。在带有丙氨酸或脯氨酸取代的分离的p27域中，特别是预先形成的＃alpha＃-螺旋的稳定性增加或降低，都不会以能量的形式影响p27抑制的环状A-Cdk2复合物的形成。然而，用丙氨酸稳定螺旋在动力学上阻碍了被抑制复合物的形成，表明p27从内在结构紊乱中获得了动力学优势。

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