Institute for Quantum Biology, National Institutes for Quantum Science and Technology, 2-4 Shirakata, Tokai, Ibaraki 319-1106, Japan.
Medicina (Kaunas). 2022 Jun 13;58(6):795. doi: 10.3390/medicina58060795.
: Intrinsically disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) are known to be involved in various human diseases. Since the IDPs/IDRs are fluctuating between many structural substrates, the dynamical behavior of the disease-related IDPs/IDRs needs to be characterized to elucidate the mechanisms of the pathogenesis of the diseases. As protein motions have a hierarchy ranging from local side-chain motions, through segmental motions of loops or disordered regions, to diffusive motions of entire molecules, segmental motions, as well as local motions, need to be characterized. : Combined analysis of quasielastic neutron scattering (QENS) spectra with the structural data provides information on both the segmental motions and the local motions of the IDPs/IDRs. Here, this method is applied to re-analyze the QENS spectra of the troponin core domain (Tn-CD), various mutants of which cause the pathogenesis of familial cardiomyopathy (FCM), and α-synuclein (αSyn), amyloid fibril formation of which is closely related to the pathogenesis of Parkinson's disease, collected in the previous studies. The dynamical behavior of wild-type Tn-CD, FCM-related mutant Tn-CD, and αSyn in the different propensity states for fibril formation is characterized. : In the Tn-CD, the behavior of the segmental motions is shown to be different between the wild type and the mutant. This difference is likely to arise from changes in the intramolecular interactions, which are suggested to be related to the functional aberration of the mutant Tn-CD. In αSyn, concerted enhancement of the segmental motions and the local motions is observed with an increased propensity for fibril formation, suggesting the importance of these motions in fibril formation. : Characterization of the segmental motions as well as the local motions is thus useful for discussing how the changes in dynamical behavior caused by the disease-related mutations and/or environmental changes could be related to the functional and/or behavioral aberrations of these proteins.
：无序蛋白（IDPs）和含有无序区域的蛋白（IDRs）已知与各种人类疾病有关。由于 IDPs/IDRs 在许多结构底物之间波动，因此需要对与疾病相关的 IDPs/IDRs 的动力学行为进行特征描述，以阐明疾病发病机制的机制。由于蛋白质运动具有从局部侧链运动到环或无序区域的片段运动，再到整个分子的扩散运动的层次结构，因此需要对片段运动以及局部运动进行特征描述。：结合准弹性中子散射（QENS）谱与结构数据的综合分析为 IDPs/IDRs 的片段运动和局部运动提供了信息。在这里，该方法应用于重新分析先前研究中收集的肌钙蛋白核心结构域（Tn-CD）的 QENS 谱，其各种突变导致家族性心肌病（FCM）的发病机制，以及与帕金森病发病机制密切相关的α-突触核蛋白（αSyn）的淀粉样纤维形成。在不同纤维形成倾向状态下，野生型 Tn-CD、FCM 相关突变 Tn-CD 和 αSyn 的动力学行为得到了特征描述。：在 Tn-CD 中，发现野生型和突变型之间的片段运动行为存在差异。这种差异可能源于分子内相互作用的变化，这些变化与突变 Tn-CD 的功能异常有关。在 αSyn 中，随着纤维形成倾向的增加，观察到片段运动和局部运动的协同增强，这表明这些运动在纤维形成中很重要。：因此，对片段运动和局部运动进行特征描述有助于讨论由疾病相关突变和/或环境变化引起的动力学行为变化如何与这些蛋白质的功能和/或行为异常相关。
