Motor proteins are active enzymatic molecules that are
critically important for a variety of biological phenomena. It is known
that some neurodegenerative diseases are caused by specific mutations
in motor proteins that lead to their malfunctioning. Hereditary spastic
paraplegia is one of such diseases, and it is associated with the mutations
in the neuronal conventional kinesin gene, producing the decreased
speed and processivity of this motor protein. Despite the importance of
this problem, there is no clear understanding on the role of mutations in
modifying dynamic properties of motor proteins. In this work, we
investigate theoretically the molecular basis for negative effects of two
specific mutations, N256S and R280S, on the dynamics of kinesin
motor proteins. We hypothesize that these mutations might accelerate
the adenosine triphosphate (ATP) release by increasing the probability
of open conformations for the ATP-binding pocket. Our approach is
based on the use of coarse-grained structure-based molecular dynamics simulations to analyze the conformational changes and
chemical transitions in the kinesin molecule, which is also supplemented by investigation of a mesoscopic discrete-state stochastic
model. Computer simulations suggest that mutations N256S and R280S can decrease the free energy difference between open
and closed biochemical states, making the open conformation more stable and the ATP release faster, which is in agreement with
our hypothesis. Furthermore, we show that in the case of N256S mutation, this effect is caused by disruption of interactions
between α helix and switch I and loop L11 structural elements. Our computational results are qualitatively supported by the
explicit analysis of the discrete-state stochastic model.
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Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control
Kinesin 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.
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- NSF-PAR ID:
- 10416884
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 120
- Issue:
- 1
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.2215170120
