Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control

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dc.citation.articleNumbere2215170120en_US
dc.citation.issueNumber1en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber120en_US
dc.contributor.authorManna, Rabindra Nathen_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorJana, Bimanen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2023-01-27T14:47:31Zen_US
dc.date.available2023-01-27T14:47:31Zen_US
dc.date.issued2023en_US
dc.description.abstractKinesin motor proteins perform several essential cellular functions powered by the adenosine triphosphate (ATP) hydrolysis reaction. Several single-point mutations in the kinesin motor protein KIF5A have been implicated to hereditary spastic paraplegia disease (HSP), a lethal neurodegenerative disease in humans. In earlier studies, we have shown that a series of HSP-related mutations can impair the kinesin’s long-distance displacement or processivity by modulating the order–disorder transition of the linker connecting the heads to the coiled coil. On the other hand, the reduction of kinesin’s ATP hydrolysis reaction rate by a distal asparagine-to-serine mutation is also known to cause HSP disease. However, the molecular mechanism of the ATP hydrolysis reaction in kinesin by this distal mutation is still not fully understood. Using classical molecular dynamics simulations combined with quantum mechanics/molecular mechanics calculations, the pre-organization geometry required for optimal hydrolysis in kinesin motor bound to α/β-tubulin is determined. This optimal geometry has only a single salt-bridge (of the possible two) between Arg203-Glu236, putting a reactive water molecule at a perfect position for hydrolysis. Such geometry is also needed to create the appropriate configuration for proton translocation during ATP hydrolysis. The distal asparagine-to-serine mutation is found to disrupt this optimal geometry. Therefore, the current study along with our previous one demonstrates how two different effects on kinesin dynamics (processivity and ATP hydrolysis), caused by a different set of genotypes, can give rise to the same phenotype leading to HSP disease.en_US
dc.identifier.citationManna, Rabindra Nath, Onuchic, José N. and Jana, Biman. "Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control." <i>Proceedings of the National Academy of Sciences,</i> 120, no. 1 (2023) PNAS: https://doi.org/10.1073/pnas.2215170120.en_US
dc.identifier.digitalpnas-2215170120en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2215170120en_US
dc.identifier.urihttps://hdl.handle.net/1911/114284en_US
dc.language.isoengen_US
dc.publisherPNASen_US
dc.rightsThis article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleRoad-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere controlen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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