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首页> 外文期刊>Cell cycle >Modulation of the p53-MDM2 interaction by phosphorylation of Thr18: a computational study.
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Modulation of the p53-MDM2 interaction by phosphorylation of Thr18: a computational study.

机译：Thr18磷酸化对p53-MDM2相互作用的调节：一项计算研究。

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摘要

The transcription factor p53 is under negative regulation by the ubiquitin ligase MDM2 and its close homologue MDM4. In the bound complex between MDM2 and p53, the transactivation domain of p53 adopts an amphipathic helical conformation which optimizes the spatial organization of three key hydrophobic residues (Phe19, Trp23, Leu26) for maximum interactions. The interaction with MDM2 is known to be abrogated by phosphorylation of Ser/Thr residues in the MDM2 N-terminal domain and in the p53 transactivation domain. In the latter, phosphorylation of Thr18 has been attributed to destabilize a key hbond between Thr18 and Asp21. This interaction has been thought to be critical for the formation of the helical conformation of the p53 transactivation domain. Molecular dynamics simulations of the p53 transactivation domain suggest that phosphorylation of either Thr18 or Ser20 does not disrupt its helical structure but does result in reduced affinities for MDM2. While interactions between the Thr18 and Asp21 areindeed broken due to charge-charge repulsions, the peptide has enough inherent flexibility to form alternate patterns of hbonds, resulting in the maintenance of helicity. Electrostatics of MDM2 reveal local anionic patches in the region where Thr18 docks. These suggest that repulsions will arise because the MDM2 surface will force the p53 to bind in a manner that will place the negatively charged phosphorylated Thr18 near this anionic region. A similar, albeit somewhat attenuated pattern of electrostatic modulations, is seen for a model of MDM4 that has been built. Mutants of MDM2 and MDM4 have been designed to attenuate this anionicity and have been computationally demonstrated to enhance the binding of the phosphorylated peptides.
机译：转录因子p53受泛素连接酶MDM2及其紧密同源物MDM4的负调控。在MDM2和p53之间的结合复合物中，p53的反式激活域采用两亲性螺旋构象，该构象优化了三个关键疏水残基（Phe19，Trp23，Leu26）的空间组织，以实现最大的相互作用。已知通过MDM2 N末端结构域和p53反式激活结构域中的Ser / Thr残基的磷酸化可以消除与MDM2的相互作用。在后者中，Thr18的磷酸化被归因于使Thr18和Asp21之间的键键不稳定。人们认为这种相互作用对于p53反式激活结构域的螺旋构象的形成至关重要。 p53反式激活域的分子动力学模拟表明，Thr18或Ser20的磷酸化不会破坏其螺旋结构，但会导致MDM2亲和力降低。虽然Thr18和Asp21之间的相互作用确实由于电荷排斥而中断，但该肽具有足够的固有柔性以形成交替的键合模式，从而维持了螺旋度。 MDM2的静电揭示了Thr18停靠区域的局部阴离子斑块。这些表明斥力将出现，因为MDM2表面将迫使p53以将带负电荷的磷酸化Thr18置于该阴离子区域附近的方式结合。对于已构建的MDM4模型，可以看到类似的静电调制模式，尽管有些减弱。 MDM2和MDM4的突变体已被设计为减弱这种阴离子性，并已通过计算证明可增强磷酸化肽的结合。

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