Identification of a Function-Specific Mutation of Clathrin Heavy Chain (CHC) Required for p53 Transactivation
Identification of a Function-Specific Mutation of Clathrin Heavy Chain (CHC) Required for p53 Transactivation
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DOI：
10.1016/j.jmb.2009.09.029
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发表时间：
2009-12-04
影响因子：
5.6
通讯作者：
Enari, Masato
中科院分区：
文献类型：
--
作者：
Ohata, Hirokazu;Ota, Nobuyuki;Enari, Masato
p53通路响应于各种细胞应激而被激活，以保护细胞免于恶性转化。我们以前已经表明，网格蛋白重链（CHC），这是一种胞质蛋白调节内吞作用，存在于细胞核中，并结合p53，以促进p53介导的转录。然而，p53和CHC之间的结合界面的细节仍不清楚。在这里，我们报告的p53和CHC之间的结合模式，使用突变分析和分子动力学产生的相互作用的结构模型。结构建模分析预测，CHC中的Asn1288残基对于与p53结合至关重要。事实上，将CHC的Asn替换为Ala降低了其与p53相互作用的能力，导致反式激活p53的活性降低。令人惊讶的是，这种突变对受体介导的内吞作用几乎没有影响。因此，CHC的功能特异性突变将阐明CHC在p53通路调节中的生理作用。(C)2009爱思唯尔有限公司版权所有。
The p53 pathway is activated in response to various cellular stresses to protect cells from malignant transformation. We have previously shown that clathrin heavy chain (CHC), which is a cytosolic protein regulating endocytosis, is present in nuclei and binds to p53 to promote p53-mediated transcription. However, details of the binding interface between p53 and CHC remain unclear. Here, we report on the binding mode between p53 and CHC using mutation analyses and a structural model of the interaction generated by molecular dynamics. Structural modeling analyses predict that an Asn1288 residue in CHC is crucial for binding to p53. In fact, substitution of this Asn to Ala of CHC diminished its ability to interact with p53, leading to reduced activity to transactivate p53. Surprisingly, this mutation had little effect on receptor-mediated endocytosis. Thus, the function-specific mutation of CHC will clarify physiological roles of CHC in the regulation of the p53 pathway. (C) 2009 Elsevier Ltd. All rights reserved.