Computational analysis of hereditary spastic paraplegia mutations in the kinesin motor domains of KIF1A and KIF5A
Computational analysis of hereditary spastic paraplegia mutations in the kinesin motor domains of KIF1A and KIF5A
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DOI：
10.1142/s0219633620410035
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发表时间：
2020-09-01
影响因子：
2.4
通讯作者：
Teng, Shaolei
中科院分区：
文献类型：
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作者：
Mahase, Vidhyanand;Sobitan, Adebiyi;Teng, Shaolei
遗传性痉挛性截瘫（HSP）是一种遗传异质性的神经退行性疾病的集合，分类为进行性下肢痉挛和虚弱。复杂HSP形式的特征在于各种神经学特征，包括进行性痉挛性无力、尿道括约肌功能障碍、锥体外系征和智力残疾（ID）。驱动蛋白超家族蛋白（KIFs）是微管依赖性的分子马达，参与细胞内的运输。驱动蛋白可定向转运膜囊泡、蛋白复合物和沿着突起的mRNA，在神经元的发育和功能中发挥重要作用。最近的遗传学研究已经确定了HSP患者的驱动蛋白突变。在这项研究中，我们使用计算的方法来调查与HSP和ID相关的KIF 1A和KIF 5A的40个错义突变。通过同源模建构建了驱动蛋白-微管结合域和驱动蛋白-微管蛋白复合物的结构。我们应用基于结构的能量计算方法来确定错义突变对蛋白质稳定性和蛋白质-蛋白质相互作用的影响。结果表明，大多数致病突变可改变驱动蛋白运动域的折叠自由能和驱动蛋白-微管蛋白复合物的结合自由能。我们发现KIF 1A中与ID相关的E253 K降低了驱动蛋白马达结构域的蛋白质稳定性。我们发现，位于驱动蛋白-微管蛋白复合物界面的HSP突变，如KIF 5A中的K253 N和R280 C，可以使驱动蛋白-微管蛋白复合物不稳定。计算分析为理解驱动蛋白突变在ID和HSP发生中的作用提供了有用的信息。
Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous collection of neurodegenerative disorders categorized by progressive lower-limb spasticity and frailty. The complex HSP forms are characterized by various neurological features including progressive spastic weakness, urinary sphincter dysfunction, extra pyramidal signs and intellectual disability (ID). The kinesin superfamily proteins (KIFs) are microtubule-dependent molecular motors involved in intracellular transport. Kinesins directionally transport membrane vesicles, protein complexes, and mRNAs along neurites, thus playing important roles in neuronal development and function. Recent genetic studies have identified kinesin mutations in patients with HSPs. In this study, we used the computational approaches to investigate the 40 missense mutations associated with HSP and ID in KIF1A and KIF5A. We performed homology modeling to construct the structures of kinesin-microtubule binding domain and kinesin-tubulin complex. We applied structure-based energy calculation methods to determine the effects of missense mutations on protein stability and protein-protein interaction. The results revealed that the most of disease-causing mutations could change the folding free energy of kinesin motor domain and the binding free energy of kinesin-tubulin complex. We found that E253K associated with ID in KIF1A decrease the protein stability of kinesin motor domains. We showed that the HSP mutations located in kinesin-tubulin complex interface, such as K253N and R280C in KIF5A, can destabilize the kinesin-tubulin complex. The computational analysis provides useful information for understanding the roles of kinesin mutations in the development of ID and HSPs.