Allosterically Regulated Structural Fluctuation And Microtubule-Binding Affinity Of Kif1a-A Simulation Study Of Coarse-Grained Model -

Kinesins are a family of molecular motor proteins that exhibit unidirectional processive motion along the microtubules using the free energy released during the ATP hydrolysis cycle. Kinesin switches its microtuble (MT) binding affinity between strong binding mode and weak binding mode depending on nucleotide states.The allosteric regulation mechanism for this switching, however, is yet to be determined. For understanding this mechanism, we focus on the single-headed kinesin called KIF1A and studied the structural fluctuations of its motor head in different nucleotide states using computer simulations.We constructed a coarse-grained Go-like model for each nucleotide state based on the X-ray structure of KIF1A that binds the corresponding nucleotide analog. Langevin dynamics simulations were used to investigate the structural fluctuations when MT is absent. We found that the helix alpha-4 at the MT binding site intermittently exhibits abrupt large structural fluctuations, actually partial unfolding and folding, which we call as “burst”. Frequency of the burst varies systematically according to the nucleotide states and correlates strongly with the experimentally observed binding affinity to MT. Namely, the binding site becomes more flexible in the strong binding state than in the weak binding state in the absence of MT.Based on this simulation result, we propose the following mechanism for the MT affinity regulation of KIF1A: (1) the flexibility of the MT binding site (helix alpha-4 in particular) is allosterically controlled according to the nucleotide states during the ATP hydrolysis process, (2) the affinity to MT is regulated through the flexibility of the MT binding site, and (3) the more flexible the MT biniding site is, the stronger the binding affinity becomes.