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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >DNA search efficiency is modulated by charge composition and distribution in the intrinsically disordered tail
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DNA search efficiency is modulated by charge composition and distribution in the intrinsically disordered tail

机译：DNA搜索效率受本征无序尾巴中电荷组成和分布的调节

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摘要

Intrinsically disordered tails are common in DNA-binding proteins and can affect their search efficiency on nonspecific DNA by promoting the brachiation dynamics of intersegment transfer. During brachiation, the protein jumps between distant DNA regions via an intermediate state in which the tail and globular moieties are bound to different DNA segments. While the disordered tail must be long and positively charged to facilitate DNA search, the effect of its residue sequence on brachiation is unknown. We explored this issue using the NK-2 and Antp homeodomain transcription factors. We designed 566 NK-2 tail-variants and 55 Antp tail-variants having different net charges and positive charge distributions and studied their dynamics and DNA search efficiencies using coarse-grained molecular dynamics simulations. More intersegment transfers occur when the tail is moderately positively charged and the positive charges are clustered together in the middle of the tail or towards its N terminus. The presence of a negatively charged residue does not significantly affect protein brachiation, although it is likely that the presence of many negatively charged residues will complicate the DNA search mechanism. A bioinformatic analysis of 1,384 wild-type homeodomains illustrates that the charge composition and distribution in their N-tail sequences are consistent with an optimal charge pattern to promote intersegment transfer. Our study thus indicates that the residue sequence of the disordered tails of DNA-binding proteins has unique characteristics that were evolutionarily selected to achieve optimized function and suggests that the sequence-structure-function paradigm known for structured proteins is valid for intrinsically disordered proteins as well.
机译：本质上无序的尾巴在DNA结合蛋白中很常见，并且可以通过促进节间转移的分支动力学来影响它们在非特异性DNA上的搜索效率。在分支过程中，蛋白质通过中间状态在远处的DNA区域之间跳跃，在中间状态下，尾部和球状部分与不同的DNA片段结合。尽管无序的尾巴必须长且带正电荷以促进DNA搜索，但其残基序列对肱骨的影响尚不清楚。我们使用NK-2和Antp同源域转录因子探讨了这个问题。我们设计了566个NK-2尾变体和55个Antp尾变体，它们具有不同的净电荷和正电荷分布，并使用粗粒度的分子动力学模拟研究了它们的动力学和DNA搜索效率。当尾部带有适度的正电荷，且正电荷在尾部中部或其N端聚集在一起时，会发生更多的节间转移。带负电残基的存在不会显着影响蛋白质的分支，尽管可能存在许多带负电残基会使DNA搜索机制复杂化。对1,384个野生型同源域的生物信息学分析表明，其N尾序列中的电荷组成和分布与促进段间转移的最佳电荷模式一致。因此，我们的研究表明，DNA结合蛋白无序尾部的残基序列具有独特的特征，这些特征经过进化选择以获得最佳功能，并表明结构蛋白已知的序列-结构-功能范式也适用于内在无序的蛋白。

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