I. Derényi, A. Czövek, G. Szollosi
Feb 1, 2009
Kinesin is a microtubule-associated motor protein which converts chemical energy (stored in ATP molecules) into mechanical work (by transporting cargo). The protein is a dimer and is believed to use its two identical motor domains (heads) alternatively to move along microtubules (MTs), reminiscent of “walking”. Although over the past decade much has been learned about the structure and kinetics of the individual kinesin heads, how two of such heads can coordinate their motion during walking is still poorly understood. The most plausible hypothesis is that the heads communicate through a mechanical force mediated by the neck linkers (short peptide chains stretching between the heads and the dimeric coiled-coil tail). Indeed, during a catalytic cycle each neck linker can dock to and undock from its own head domain, indicating that the relative frequencies of these conformations and the rates of the corresponding transitions are strongly dependent on the position of the other head, providing a key to coordination.By considering the two neck linkers as entropic springs and incorporating the most relevant kinetic and structural properties of the individual heads, we have constructed the first detailed, thermodynamically consistent model of dimeric kinesin that can (i) explain the cooperative motion of the heads during walking and (ii) reproduce much of the available experimental data (speed, dwell time distribution, randomness, processivity, hydrolysis rate, etc.) under a wide range of conditions (nucleotide concentrations, loading force, neck linker length and composition, etc.) simultaneously. Apart from revealing the mechanism by which kinesin operates, our model also allows us to look into the experimentally inaccessible details of the mechanochemical cycle and predict how certain changes in the protein would affect its motion.