Nucleotide-dependent structural fluctuations and regulation of microtubule-binding affinity of KIF1A

Abstract

Molecular motors such as kinesin regulate affinity to a rail protein during the ATP hydrolysis cycle. The regulation mechanism, however, is yet to be determined. To understand this mechanism, we investigated the structural fluctuations of the motor head of the single-headed kinesin called KIF1A in different nucleotide states using molecular dynamics simulations of a Gō-like model. We found that the helix α4 at the microtubule (MT) binding site intermittently exhibits a large structural fluctuation when MT is absent. Frequency of this fluctuation changes systematically according to the nucleotide states and correlates strongly with the experimentally observed binding affinity to MT. We also showed that thermal fluctuation enhances the correlation and the interaction with the nucleotide suppresses the fluctuation of the helix α4. These results suggest that KIF1A regulates affinity to MT by changing the flexibility of the helix α4 during the ATP hydrolysis process: the binding site becomes more flexible in the strong binding state than in the weak binding state.

A de novo low‐frequency mosaic variant of KIF1A causes hereditary spastic paraplegia: A literature review

“…The NC attached to the MD undergoes different conformational changes under different ATP binding states and generates changes in tension through binding and separation from the MD. The CC1‐FHA‐CC2‐CC3 region is located in the middle of the protein and is associated with the formation of regulatory kinesin dimers (Kanada et al., 2015; Morikawa et al., 2022). The PH domain recognizes the organelle being transported (Guo et al., 2020).…”

Investigating role of conformational changes of microtubule in regulating its binding affinity to kinesin by all‐atom molecular dynamics simulation

“…Molecular dynamics (MDs) simulations, including coarse-grained modeling [22][23][24][25][26][27] and all-atom molecular simulation, [28][29][30] are powerful methods to provide dynamic information of kinesin motor function, which are complementary to X-ray crystallography and cryo-electron microscopy (cryo-EM) to provide static information. Using all-atom MD simulations, the mechanism and dynamics of neck-linker docking into its motor domain, which plays an important role in kinesin motion, were investigated.…”