Department of Biosciences and Nutrition, Karolinska Institutet, Neo, TTI, SE-141 83 Huddinge, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Neo, TTI, SE-141 83 Huddinge, Sweden.
Biochim Biophys Acta Gen Subj. 2018 Jun;1862(6):1452-1461. doi: 10.1016/j.bbagen.2018.03.015. Epub 2018 Mar 14.
Adaptive mutations that alter protein functionality are enriched within intrinsically disordered protein regions (IDRs), thus conformational flexibility correlates with evolvability. Pre-structured motifs (PreSMos) with transient propensity for secondary structure conformation are believed to be important for IDR function. The glucocorticoid receptor tau1core transcriptional activation domain (GR tau1core) domain contains three α-helical PreSMos in physiological buffer conditions.
Sixty change-of-function mutants affecting the intrinsically disordered 58-residue GR tau1core were studied using disorder prediction and molecular dynamics simulations.
Change-of-function mutations were partitioned into seven clusters based on their effect on IDR predictions and gene activation activity. Some mutations selected from clusters characterized by mutations altering the IDR prediction score, altered the apparent stability of the α-helical form of one of the PreSMos in molecular dynamics simulations, suggesting PreSMo stabilization or destabilization as strategies for functional adaptation. Indeed all tested gain-of-function mutations affecting this PreSMo were associated with increased stability of the α-helical PreSMo conformation, suggesting that PreSMo stabilization may be the main mechanism by which adaptive mutations can increase the activity of this IDR type. Some mutations did not appear to affect PreSMo stability.
Changes in PreSMo stability account for the effects of a subset of change-of-function mutants affecting the GR tau1core IDR.
Long IDRs occur in about 50% of human proteins. They are poorly characterized despite much recent attention. Our results suggest the importance of a subtle balance between PreSMo stability and IDR activity, which may provide a novel target for future pharmaceutical intervention.
改变蛋白质功能的适应性突变在无序蛋白质区域（IDR）中富集，因此构象灵活性与可进化性相关。具有瞬态二级结构构象倾向的预结构基序（PreSMos）被认为是 IDR 功能的重要组成部分。糖皮质激素受体 tau1 核心转录激活结构域（GR tau1core）域在生理缓冲条件下包含三个α-螺旋 PreSMos。
使用无序预测和分子动力学模拟研究了影响 58 个残基无序 GR tau1core 的 60 个功能变化突变体。
根据对 IDR 预测和基因激活活性的影响，将功能变化突变体分为七个簇。从 IDR 预测评分改变的特征聚类中选择的一些突变改变了 PreSMos 之一的α-螺旋形式的表观稳定性，这表明 PreSMo 稳定或不稳定是功能适应的策略。事实上，所有测试的影响此 PreSMo 的获得功能突变都与α-螺旋 PreSMo 构象的稳定性增加有关，这表明 PreSMo 稳定可能是适应性突变可以增加这种 IDR 类型活性的主要机制。一些突变似乎不影响 PreSMo 的稳定性。
PreSMo 稳定性的变化解释了影响 GR tau1core IDR 的部分功能变化突变体的影响。
长 IDR 出现在大约 50%的人类蛋白质中。尽管最近引起了很多关注，但它们的特征仍不清楚。我们的结果表明 PreSMo 稳定性和 IDR 活性之间的微妙平衡很重要，这可能为未来的药物干预提供新的目标。
