Conformational effects of a common codon 399 polymorphism on the BRCT1 domain of the XRCC1 protein
Conformational effects of a common codon 399 polymorphism on the BRCT1 domain of the XRCC1 protein
复制标题
DOI：
10.1007/s10930-007-9095-y
复制
发表时间：
2007-12-01
期刊：
影响因子：
3
通讯作者：
Brandt-Rauf, Paul W.
中科院分区：
文献类型：
--
作者：
Monaco, Regina;Rosal, Ramon;Brandt-Rauf, Paul W.
x射线交叉互补-1 （XRCC1）蛋白作为一种支架，在DNA损伤的碱基切除修复（BER）过程中协调细胞机制的活性。XRCC1的BRCT1结构域负责与BER机制的几个关键组分相互作用，它也是XRCC1中氨基酸残基399 （Arg -> Gln）的常见遗传多态性位点。实验和流行病学证据表明，这种多态性可能改变BER能力，增加癌症风险。本研究的目的是探讨这些影响是否可归因于多态性诱导的XRCC1构象变化。利用分子动力学技术预测了XRCC1基因BRCT1结构域的野生型和多态性形式，并确定了多态性取代所产生的结构差异。结果表明，尽管这两种蛋白质的一般结构相似，并且在多态性本身的位点上几乎没有实际偏差，但这种替代在BRCT1结构域的其他几个位点上产生了显著的构象变化，包括二级结构特征的丧失，例如可能对蛋白质-蛋白质相互作用至关重要的螺旋。这些结果支持了XRCC1的多态性可能通过改变BRCT1结构域的结构从而影响DNA修复能力的假设，从而影响XRCC1协调BER的能力。
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 a 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.