Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.
Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.
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烷基转移酶样蛋白 (Atl1) 通过阳离子-β 相互作用区分用于 DNA 修复的烷基化鸟嘌呤。
DOI：
10.1073/pnas.1209451109
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发表时间：
2012
影响因子：
11.1
通讯作者：
Hunter,Christopher
中科院分区：
文献类型：
--
作者：
Wilkinson,OliverJ;Latypov,Vitaly;Tubbs,JulieL;Millington,ChristopherL;Morita,Rihito;Blackburn,Hannah;Marriott,Andrew;McGown,Gail;Thorncroft,Mary;Watson,AmandaJ;Connolly,BernardA;Grasby,JaneA;Masui,Ryoji;Hunter,Christopher
粟酒裂殖酵母（Schizosophyomycespombe）和嗜热栖热菌（Thermusthermophilus）中的烷基转移酶样（ATL）蛋白通过标记O 6-烷基鸟嘌呤损伤以进行核苷酸切除修复（NER）来保护DNA免受烷基化损伤的不利影响。我们发现，这两个ATL蛋白结合具有高亲和力的寡脱氧核糖核苷酸containingO 6-烷基鸟嘌呤不同的大小，极性和电荷的烷基。然而，THA 1显示出比TTHA 1564更大的能力来区分O 6-alkylguanine和鸟嘌呤，并在一个前所未有的机制使用Arg 69探测静电势面ofO 6-alkylguanine，确定使用分子力学计算。这一特征的一个意想不到的结果是2，6-二氨基嘌呤和2-氨基嘌呤的识别，如在相应的R69 A和R69 F突变体和S的R69 A和R69 F突变体的晶体结构中所证实的。pombeR 69 A和R69 F突变体对烷化剂毒性更敏感，揭示了Arg 69在识别NER识别关键的O 6-烷基鸟嘌呤中的关键作用。
Alkyltransferase-like (ATL) proteins inSchizosaccharomyces pombe(Atl1) andThermus thermophilus(TTHA1564) protect against the adverse effects of DNA alkylation damage by flaggingO6-alkylguanine lesions for nucleotide excision repair (NER). We show that both ATL proteins bind with high affinity to oligodeoxyribonucleotides containingO6-alkylguanines differing in size, polarity, and charge of the alkyl group. However, Atl1 shows a greater ability than TTHA1564 to distinguish betweenO6-alkylguanine and guanine and in an unprecedented mechanism uses Arg69 to probe the electrostatic potential surface ofO6-alkylguanine, as determined using molecular mechanics calculations. An unexpected consequence of this feature is the recognition of 2,6-diaminopurine and 2-aminopurine, as confirmed in crystal structures of respective Atl1-DNA complexes.O6-Alkylguanine and guanine discrimination is diminished for Atl1 R69A and R69F mutants, andS. pombeR69A and R69F mutants are more sensitive toward alkylating agent toxicity, revealing the key role of Arg69 in identifyingO6-alkylguanines critical for NER recognition.