Molecular Motors: Subdomain Dynamics and Mechanochemistry

Abstract

Biological cells contain nano-molecular motors that perform essential functions such as intracellular transport, muscle contraction, and chromosome separation. Molecular motors are enzymatic proteins that drive the intracellular trafficking by converting the chemical energy of adenosine triphosphate (ATP) hydrolysis into mechanical action. Among different motor proteins coexisting in every eukaryotic cell, cytoplasmic motor proteins are plausibly most fascinating. These proteins bind to a polarized cytoskeleton filament, move unidirectionally and divided into three motor classes: myosins, which move on actin filaments, and dyneins and kinesins, which use microtubules (MT) as tracks. ATP hydrolysis alters their subdomain dynamics in the catalytic domain which is further communicated to the track-binding site. This chapter will focus on kinesins, the structural and molecular basis of force generation, how they differ markedly from myosins and dyneins and, insights into their remarkable motor mechanochemistry. We will discuss the core architecture and structural elements of kinesin and how the intramolecular communication within the kinesin motor domain translates into a large conformational change that leads to a directional movement along the microtubule track. Concomitantly, recent findings of the bidirectional motility of kinesin-5 motors will also be discussed in detail that is contrary to the previous dogma of unidirectional movement of plus end-directed molecular motors. We will also substantiate several structural determinants of kinesin-5 motors that regulate directional switching along with the evidence of cover-neck bundle formation in yeast kinesin-5 that is well established for the plus end-directed movement in kinesin-1 motors. Further, we brief about some small molecule inhibitors that bind to Loop5 of kinesin-5 and affect the subdomain dynamics and important for anti-cancer treatment. The understanding of structural and biophysical dynamics of kinesin motors could be helpful to elucidate how these motors function during mitosis and the molecular mechanism of bidirectionality and force generation.