Monaco Regina, Rosal Ramon, Dolan Michael A, Pincus Matthew R, Brandt-Rauf Paul W
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY 10032, USA.
Protein J. 2007 Dec;26(8):541-6. doi: 10.1007/s10930-007-9095-y.
The X-ray cross-complementing-1 (XRCC1) protein functions as a scaffold that coordinates the activity of the cellular machinery involved in base excision repair (BER) of DNA damage. The BRCT1 domain of XRCC1 is responsible for interacting with several of the key components of the BER machinery, and it is also the site of a common genetic polymorphism in XRCC1 at amino acid residue 399 (Arg --> Gln). Experimental and epidemiologic evidence suggest that this polymorphism may alter BER capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XRCC1 induced by the polymorphism. Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the BRCT1 domain of XRCC1, and differences in structure produced by the polymorphic substitution were determined. The results indicate that, although the general configuration of both proteins is similar and there is little actual deviation at the site of the polymorphism itself, the substitution produces significant conformational changes at several other sites in the BRCT1 domain, including the loss of secondary structural features such as alpha helices that may be critical for protein-protein interactions. These results provide support for the hypothesis that this polymorphism in XRCC1 could affect DNA repair capability by altering the structure of the BRCT1 domain and thus the ability of XRCC1 to coordinate BER.
X射线交叉互补蛋白1（XRCC1）作为一种支架蛋白，可协调参与DNA损伤碱基切除修复（BER）的细胞机制的活性。XRCC1的BRCT1结构域负责与BER机制的几个关键组分相互作用，并且它也是XRCC1中位于氨基酸残基399处（精氨酸→谷氨酰胺）常见基因多态性的位点。实验和流行病学证据表明，这种多态性可能会改变BER能力并增加癌症风险。本研究的目的是调查这些效应是否可归因于该多态性诱导的XRCC1构象变化。使用分子动力学技术预测XRCC1的BRCT1结构域野生型和多态型的结构，并确定多态性取代产生的结构差异。结果表明，虽然两种蛋白质的总体构型相似，并且在多态性位点本身几乎没有实际偏差，但该取代在BRCT1结构域的其他几个位点产生了显著的构象变化，包括二级结构特征（如可能对蛋白质-蛋白质相互作用至关重要的α螺旋）的丧失。这些结果为以下假设提供了支持：XRCC1中的这种多态性可能通过改变BRCT1结构域的结构从而改变XRCC1协调BER的能力来影响DNA修复能力。
