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.
Missense Mutations of Human Hsp60: A Computational Analysis to Unveil Their Pathological Significance
