Oxidation state of the XRCC1 N-terminal domain regulates DNA polymerase β binding affinity
Oxidation state of the XRCC1 N-terminal domain regulates DNA polymerase β binding affinity
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DOI：
10.1073/pnas.0914077107
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发表时间：
2010-04-13
影响因子：
11.1
通讯作者：
London, Robert E.
中科院分区：
文献类型：
--
作者：
Cuneo, Matthew J.;London, Robert E.
XRCC1 N末端结构域(NTD)和DNA聚合酶β(POLβ)之间形成的复合体是损伤DNA碱基切除修复的核心。对XRCC1-NTD与Polβ络合物的两种晶型进行了解析，发现XRCC1-NTD能够采用氧化还原相关的交替折叠，其特征是二硫键，二级结构、折叠拓扑结构和静电表面都发生了很大的变化。尽管这些结构变化大多发生在界面的远端，但氧化的XRCC1-NTD与POLβ形成了额外的相互作用，使亲和力提高了一个数量级。瞬时二硫键的形成被认为是一种重要的分子调控机制。本文提出了DNA修复的一种范式，在该范式中，支架蛋白的氧化还原状态在组织修复复合体中起着积极的作用。
Formation of a complex between the XRCC1 N-terminal domain (NTD) and DNA polymerase beta (Pol beta) is central to base excision repair of damaged DNA. Two crystal forms of XRCC1-NTD complexed with Pol beta have been solved, revealing that the XRCC1-NTD is able to adopt a redox-dependent alternate fold, characterized by a disulfide bond, and substantial variations of secondary structure, folding topology, and electrostatic surface. Although most of these structural changes occur distal to the interface, the oxidized XRCC1-NTD forms additional interactions with Pol beta, enhancing affinity by an order of magnitude. Transient disulfide bond formation is increasingly recognized as an important molecular regulatory mechanism. The results presented here suggest a paradigm in DNA repair in which the redox state of a scaffolding protein plays an active role in organizing the repair complex.