Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.
Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.
复制标题
DOI：
10.1371/journal.pcbi.1010006
复制
发表时间：
2022-04
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
许多致病性错义突变存在于既不保守也不属于任何已知功能域的蛋白质位置。因此，我们缺乏任何机制的基础功能障碍所造成的这种突变。我们探讨了这些位置和已知的功能位点之间的变构动态耦合的破坏作为一种可能的发病机制。在这项研究中，我们提出了一个分析的591致病性错义变异144人类酶，表明变构动态耦合突变的位置与已知的活性位点是一个合理的生物物理机制和证据，其功能的重要性。我们在β-葡糖脑苷脂酶（GCase）的案例研究中说明了这一机制，其中绝大多数94个位点含有戈谢病相关的错义变体，位于距离活性位点一定距离处。GCase的构象动力学分析表明，这些远端位点上的突变导致活性位点残基的灵活性发生变化，尽管它们的距离，表明整个蛋白质的动态通信网络。由错义突变引起的长距离动态耦合的破坏可能为生物功能障碍和疾病提供一个合理的一般机制解释。遗传性疾病通常发生在蛋白质突变导致功能获得/丧失时。尽管存在几种基于保守性和蛋白质生物化学的方法来预测可能影响功能的基因突变，但这些指标仍然无法解释许多疾病相关的突变。在这项研究中，我们寻求这种疾病相关突变的机制解释。为了发挥功能，蛋白质的重要区域必须能够表现出集体运动。通过计算机模拟，我们观察到蛋白质中即使是单个氨基酸位置的突变也可以改变蛋白质的运动。我们发现，疾病相关的突变往往会改变蛋白质功能关键区域的运动，即使这些突变发生在远离这些关键区域的地方。此外，我们检查了蛋白质内两个氨基酸位置可以“偶联”的程度，即，一个位置的运动影响另一个位置的程度。我们发现，与蛋白质活性位点高度偶联的位置在突变时更有可能导致疾病，从而通过结合内部蛋白质动力学为预测新突变的发病机制提供了一种新的工具。
Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease. Genetic diseases often occur when mutations in proteins cause gain/loss of functions. Although several methods based on conservation and protein biochemistry exist to predict genetic mutations that may impact function, many disease-associated mutations remain unexplained by these metrics. In this study, we sought a mechanistic explanation for such disease-associated mutations. In order to function, important regions of a protein must be able to exhibit collective motion. Through computer simulations, we observed that mutation of even a single amino acid position within a protein can change the protein motion. We found that disease-associated mutations tend to alter the motion of regions critical to protein function, even though these mutations occur far from these critical regions. In addition, we examined the degree to which two amino acid positions within a protein may be “coupled,” i.e., the extent to which motion in one position affects the other. We found that positions highly coupled to the active site of a protein are more likely to result in disease when mutated, thereby offering a new tool for predicting pathogenesis of new mutations by incorporating internal protein dynamics.
登录
查看更多内容
影响因子：
16.8
作者：
Bhabha, Gira;Ekiert, Damian C.;Jennewein, Madeleine;Zmasek, Christian M.;Tuttle, Lisa M.;Kroon, Gerard;Dyson, H. Jane;Godzik, Adam;Wilson, Ian A.;Wright, Peter E.
通讯作者：
Wright, Peter E.
影响因子：
9.9
作者：
Clark, L. N.;Ross, B. M.;Marder, K.
通讯作者：
Marder, K.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
7.7
作者：
Dvir, H;Harel, M;Sussman, JL
通讯作者：
Sussman, JL
影响因子：
2
作者：
DAY, WHE;EDELSBRUNNER, H
通讯作者：
EDELSBRUNNER, H