title: Electrostatically biased binding of kinesin to microtubules.
abstract: The minimum motor domain of kinesin-1 is a single head. Recent evidence suggests that such minimal motor domains generate force by a biased binding mechanism, in which they preferentially select binding sites on the microtubule that lie ahead in the progress direction of the motor. A specific molecular mechanism for biased binding has, however, so far been lacking. Here we use atomistic Brownian dynamics simulations combined with experimental mutagenesis to show that incoming kinesin heads undergo electrostatically guided diffusion-to-capture by microtubules, and that this produces directionally biased binding. Kinesin-1 heads are initially rotated by the electrostatic field so that their tubulin-binding sites face inwards, and then steered towards a plus-endwards binding site. In tethered kinesin dimers, this bias is amplified. A 3-residue sequence (RAK) in kinesin helix alpha-6 is predicted to be important for electrostatic guidance. Real-world mutagenesis of this sequence powerfully influences kinesin-driven microtubule sliding, with one mutant producing a 5-fold acceleration over wild type. We conclude that electrostatic interactions play an important role in the kinesin stepping mechanism, by biasing the diffusional association of kinesin with microtubules.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics and Howard Hughes Medical Institute, University of California-San Diego, La Jolla, California, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Grant
authors.forename: Dana M
authors.initials: DM
authors.lastname: Gheorghe
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zheng
authors.forename: Maria
authors.initials: M
authors.lastname: Alonso
authors.forename: Gary
authors.initials: G
authors.lastname: Huber
authors.forename: Maciej
authors.initials: M
authors.lastname: Dlugosz
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cross
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016547:Kinesins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D016296:Mutagenesis; D055672:Static Electricity; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D014404:Tubulin; D016547:Kinesins