The kinesin molecular motors harness the chemical energy of ATP to move continuously along microtubule filaments by taking alternating steps using their dimerized catalytic domains. The mechanism by which kinesin generates force and movement remains uncertain, due in part to the inability of current methods to obtain atomic-resolution structures of this motor during its functionally critical microtubule-attached states. Here we report a series of 3D cryo-EM reconstructions that shed new light on the kinesin mechanism. We have recently overcome substantial technical hurdles in order to solve the first 3D reconstruction of dimeric kinesin captured in mid-step, where both catalytic domains are simultaneously attached at consecutive sites along the microtubule. We have also solved sub-nanometer resolution structures of a minus end-directed kinesin (ncd) in complex with the microtubule, revealing detailed conformational arrangements that reverse this motor's direction of travel relative to conventional kinesins. By combining these results with flexible fitting molecular dynamics simulations, we have derived atomic models that suggest a surprisingly simple and universal mechanism for how microtubules activate kinesin's motile functions.

Tickling the feet: A model for how microtubules trigger the enzymatic machinery of the kinesin molecular motor

245th National Meeting (2013)

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