Rational Coupled Dynamics Network Manipulation Rescues Disease-Relevant Mutant Cystic Fibrosis Transmembrane Conductance Regulator.
Rational Coupled Dynamics Network Manipulation Rescues Disease-Relevant Mutant Cystic Fibrosis Transmembrane Conductance Regulator.
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DOI：
10.1039/c4sc01320d
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发表时间：
2015-02
期刊：
影响因子：
8.4
通讯作者：
Dokholyan NV
中科院分区：
文献类型：
--
作者：
Proctor EA;Kota P;Aleksandrov AA;He L;Riordan JR;Dokholyan NV
一种新的方法，确定网络的残基参与反式蛋白质的动态耦合应用于拯救突变CFTR。生命所必需的许多细胞功能受到蛋白质变构构象变化的严格调控，并且已经发现蛋白质区域之间的相关动力学有助于以前不被认为是变构的蛋白质的功能。因此，映射和控制这种动态耦合的能力将为当前治疗设计策略的扩展创造机会。在这里，我们提出了一种方法来确定参与蛋白质相关运动转移的残基网络，并将我们的方法应用于拯救致病突变型囊性纤维化跨膜调节因子（CFTR）离子通道ΔF508和ΔI507，它们共同构成了超过90%的囊性纤维化病例。我们发现，这些突变扰动动态耦合内的第一个核苷酸结合域（NBD1），并揭示了一个关键的残基，介导跨域耦合动力学。通过合理设计该残基的突变，我们改善了突变CFTR的异常动力学，并增强了两种突变体的表面表达和功能，证明了通过合理校正异常蛋白质动力学来拯救疾病突变。
A novel approach identifying networks of residues involved in trans-protein dynamic coupling is applied to rescue mutant CFTR. Many cellular functions necessary for life are tightly regulated by protein allosteric conformational change, and correlated dynamics between protein regions has been found to contribute to the function of proteins not previously considered allosteric. The ability to map and control such dynamic coupling would thus create opportunities for the extension of current therapeutic design strategy. Here, we present an approach to determine the networks of residues involved in the transfer of correlated motion across a protein, and apply our approach to rescue disease-causative mutant cystic fibrosis transmembrane regulator (CFTR) ion channels, ΔF508 and ΔI507, which together constitute over 90% of cystic fibrosis cases. We show that these mutations perturb dynamic coupling within the first nucleotide-binding domain (NBD1), and uncover a critical residue that mediates trans-domain coupled dynamics. By rationally designing a mutation to this residue, we improve aberrant dynamics of mutant CFTR as well as enhance surface expression and function of both mutants, demonstrating the rescue of a disease mutation by rational correction of aberrant protein dynamics.