Salt bridge dynamics in protein/DNA recognition: a comparative analysis of Elk1 and ETV6.
Salt bridge dynamics in protein/DNA recognition: a comparative analysis of Elk1 and ETV6.
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DOI：
10.1039/d1cp01568k
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发表时间：
2021-06-23
期刊：
影响因子：
--
通讯作者：
Poon GMK
中科院分区：
文献类型：
--
作者：
Vo TD;Schneider AL;Wilson WD;Poon GMK
静电蛋白质/DNA相互作用源自DNA磷酸二酯骨架的中和以及作为盐作为盐桥的带电蛋白质残基或与移动的离子的偶联交换。界面离子对与DNA的相互作用已经并将继续受到人们的关注。界面外离子相互作用的作用，特别是作为DNA序列选择性的动态驱动程序，仍然知之甚少。ETS家族的转录因子代表了一个有吸引力的模型，用于解决这个知识差距，因为它们在一级结构中的离子组成不同，折叠成一个紧密保守的DNA结合基序。为了探索额外的界面盐桥在DNA识别的重要性，我们比较了盐依赖性结合Elk 1与ETV 6，两个ETS同系物不同显着的离子组成。虽然这两种蛋白质表现出盐依赖性结合同源DNA，对应于界面磷酸盐接触，其非特异性结合偏离同源结合以及彼此。分子动力学模拟明确的溶剂，产生的离子相互作用与实验结合数据一致，揭示了不同的盐桥动力学的非特异性复合物形成的两种蛋白质。受损的DNA接触ETV 6导致在非特异性复合物中的骨架接触较少，而Elk 1则通过两个ETS亲属之间不保守的残基表现出界面外盐桥的重新分布。因此，离子残基的一级结构变异可以在高度保守的DNA结合基序中编码高度分化的特异性机制。
Electrostatic protein/DNA interactions arise from the neutralization of the DNA phosphodiester backbone as well as coupled exchanges by charged protein residues as salt bridges or with mobile ions. Much focus has been and continues to be paid to interfacial ion pairs with DNA. The role of extra-interfacial ionic interactions, particularly as dynamic drivers of DNA sequence selectivity, remain poorly known. The ETS family of transcription factors represents an attractive model for addressing this knowledge gap given their diverse ionic composition in primary structures that fold to a tightly conserved DNA-binding motif. To probe the importance of extra-interfacial salt bridges in DNA recognition, we compared the salt-dependent binding by Elk1 with ETV6, two ETS homologs differing markedly in ionic composition. While both proteins exhibit salt-dependent binding with cognate DNA that corresponds to interfacial phosphate contacts, their nonspecific binding diverges from cognate binding as well as each other. Molecular dynamics simulations in explicit solvent, which generated ionic interactions in agreement with the experimental binding data, revealed distinct salt-bridge dynamics in the nonspecific complexes formed by the two proteins. Impaired DNA contact by ETV6 resulted in fewer backbone contacts in the nonspecific complex, while Elk1 exhibited a redistribution of extra-interfacial salt bridges via residues that are non-conserved between the two ETS relatives. Thus, primary structure variation in ionic residues can encode highly differentiated specificity mechanisms in a highly conserved DNA-binding motif.
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