Alpha Helices Are More Robust to Mutations than Beta Strands.
Alpha Helices Are More Robust to Mutations than Beta Strands.
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DOI：
10.1371/journal.pcbi.1005242
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发表时间：
2016-12
影响因子：
4.3
通讯作者：
Marsh JA
中科院分区：
文献类型：
--
作者：
Abrusán G;Marsh JA
关于人类遗传变异的数据量迅速增加，导致对通过计算识别致病突变的需求不断增长，因为它们的实验验证目前尚无法实现。在这里，我们表明，α螺旋和β链的耐受突变的能力显着不同：螺旋可以积累更多的突变比没有变化的链，由于螺旋中的残基间接触的数量更高。这导致两种模式：a）相同数目的突变在螺旋中比在链中引起更少的结构变化; B）螺旋在序列上比在相同结构域内的链更快地发散。此外，螺旋和股线都比卷曲明显更坚固。基于这一观察结果，我们表明，改变二级结构的人类错义突变比那些不改变二级结构的突变更有可能致病。此外，包括预测的二级结构变化显示出显着的效用，以改善国家的最先进的致病性预测。决定蛋白质的鲁棒性和可进化性的因素在很大程度上仍然是未知的。在这项工作中，作者表明蛋白质的不同二级结构元件（螺旋和链）在耐受突变的能力方面存在差异，并证明这是由这些二级结构单元内非共价残基相互作用数量的差异引起的。结果表明，从头设计全α蛋白质应该比全β蛋白质更容易，因为更多的序列可以折叠成相同的拓扑结构。此外，二级结构可用于改进目前的致病性预测方法;改变二级结构的突变比不改变二级结构的突变更可能是致病性的，因为它们对蛋白质结构具有强烈的不稳定作用。
The rapidly increasing amount of data on human genetic variation has resulted in a growing demand to identify pathogenic mutations computationally, as their experimental validation is currently beyond reach. Here we show that alpha helices and beta strands differ significantly in their ability to tolerate mutations: helices can accumulate more mutations than strands without change, due to the higher numbers of inter-residue contacts in helices. This results in two patterns: a) the same number of mutations causes less structural change in helices than in strands; b) helices diverge more rapidly in sequence than strands within the same domains. Additionally, both helices and strands are significantly more robust than coils. Based on this observation we show that human missense mutations that change secondary structure are more likely to be pathogenic than those that do not. Moreover, inclusion of predicted secondary structure changes shows significant utility for improving upon state-of-the-art pathogenicity predictions. The factors that determine the robustness and evolvability of proteins are still largely unknown. In this work the authors show that different secondary structure elements of proteins (helices and strands) differ in their ability to tolerate mutations, and demonstrate that it is caused by differences in the number of non-covalent residue interactions within these secondary structure units. The results suggest that engineering de novo all-alpha proteins should be easier than all-beta ones, as more sequences can to fold to the same topology. Additionally, secondary structure can be used to improve current methods of pathogenicity predictions; mutations that change secondary structure are more likely to be pathogenic than mutations that do not, due to their strong destabilizing effect on protein structure.
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影响因子：
6.8
作者：
Kucukkal TG;Petukh M;Li L;Alexov E
通讯作者：
Alexov E
影响因子：
8.6
作者：
England, JL;Shakhnovich, EI
通讯作者：
Shakhnovich, EI
影响因子：
4.4
作者：
Hecht M;Bromberg Y;Rost B
通讯作者：
Rost B
影响因子：
14.9
作者：
Cunningham F;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt SE;Janacek SH;Johnson N;Juettemann T;Kähäri AK;Keenan S;Martin FJ;Maurel T;McLaren W;Murphy DN;Nag R;Overduin B;Parker A;Patricio M;Perry E;Pignatelli M;Riat HS;Sheppard D;Taylor K;Thormann A;Vullo A;Wilder SP;Zadissa A;Aken BL;Birney E;Harrow J;Kinsella R;Muffato M;Ruffier M;Searle SM;Spudich G;Trevanion SJ;Yates A;Zerbino DR;Flicek P
通讯作者：
Flicek P
DOI：
10.1073/pnas.1216613110
发表时间：
2013-08-27
影响因子：
11.1
作者：
Bromberg, Yana;Kahn, Peter C.;Rost, Burkhard
通讯作者：
Rost, Burkhard