Structural consequences of hereditary spastic paraplegia disease-related mutations in kinesin

Significance Motor proteins are important biological machines responsible for cellular transport. Malfunctioning of them causes several neurodegenerative diseases. We searched for a molecular-level answer for malfunctioning kinesin, which causes hereditary spastic paraplegia (HSP) disease. Using explicit solvent simulation, the thermodynamic integration (TI) method, and bioinformatics analysis, we explored how four HSP mutants of kinesin perturb microtubule (MT) binding and motor dimerization. Taking these observations into account, we developed a coarse-grained structure-based model to reveal the effect of these mutations on kinesin’s order–disorder transition, which leads to the processivity and directionality of kinesin. Our study potentially uncovers a molecular-level picture of the role of some HSP mutants and its broad aspect in kinesin mechanochemistry. A wide range of mutations in the kinesin motor Kif5A have been linked to a neuronal disorder called hereditary spastic paraplegia (HSP). The position of these mutations can vary, and a range of different motile behaviors have been observed, indicating that the HSP mutants can alter distinct aspects of kinesin mechanochemistry. While focusing on four key HSP-associated mutants, this study examined the structural and dynamic perturbations that arise from these mutations using a series of different computational methods, ranging from bioinformatics analyses to all-atom simulations, that account for solvent effects explicitly. We show that two catalytic domain mutations (R280S and K253N) reduce the microtubule (MT) binding affinity of the kinesin head domains appreciably, while N256S has a much smaller impact. Bioinformatics analysis suggests that the stalk mutation A361V perturbs motor dimerization. Subsequent integration of these effects into a coarse-grained structure-based model of dimeric kinesin revealed that the order–disorder transition of the neck linker is substantially affected, indicating a hampered directionality and processivity of kinesin. The present analyses therefore suggest that, in addition to kinesin-MT binding and coiled-coil dimerization, HSP mutations affecting motor stepping transitions and processivity can lead to disease.

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