Kinesin: What Gives?
Steven M. Block1, ,
1 Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
Available online 29 September 2000.
Kinesin shares one or more properties with various mechanoenzymes. Like myosin, kinesin is the eponymous member of an entire superfamily of ATP-driven motors in eukaryotes: yeast has six kinesin-related proteins, and over two dozen relatives have been identified in the mouse. Like dynein, kinesin is a protein that binds to and moves along a microtubule substrate, powering a variety of transport processes, such as vesicle movement. Like many nucleic acid–based enzymes (polymerases, helicases, nucleases, etc.), but unlike myosin or dynein, kinesin functions processively, translocating through multiple enzymatic cycles before releasing from its substrate (  and  [both in this issue of Cell). However, kinesin enjoys one distinction that sets it apart from the pack. Each of its two globular heads, responsible for both enzymatic and motor activity, is formed from a single polypeptide only ∼345 amino acids long. Kinesin's motor domain weighs three times less than that of myosin (which carries two additional light chains), and ten times less than that of dynein (which carries both light and intermediate chains). As such, kinesin is the smallest molecular motor, by far—and quite possibly the simplest (for reviews, see , ,  and ). Although kinesin's discovery lagged two decades after dynein and nearly a century after myosin, our understanding of kinesin today rivals or surpasses that of any other motor protein, thanks to advances in molecular and structural biology, biophysics, and the not inconsiderable groundwork laid by prior studies of myosin. But despite the wealth of data accumulated for kinesin in just over a decade, we still don't understand the molecular mechanism by which it, or any other biological motor, moves.
Much of what we've learned about kinesin is so new that researchers have scarcely had time to digest it. Crystal structures have now been determined for the motor domains of kinesin (  and ) and family relatives ncd (Sablin et al. 1996) and Kar3p (Gulick et al. 1998). Remarkably, all three structures share a folding motif that is identical to one present in the core of the myosin head, and also to a lesser degree in G proteins, such as ras and α-transducin, raising the possibility of a common mechanism (Vale 1996). Recently, the structure of a dimeric kinesin construct was solved, revealing how its two heads are connected (Figure 1; Kozielski et al. 1997), as well as the long-sought structures for α- and β-tubulin (Nogales et al. 1998). High-resolution electron microscopic reconstructions by several groups have shown how kinesin, a plus-end directed motor, is situated when bound to microtubules, as compared to ncd, its minus-end directed cousin (Amos and Hirose 1997). These reconstructions, and studies of the directions moved by genetically engineered kinesin-ncd chimeras, have furnished early hints about the origin of directional polarity in kinesin proteins (  and ). Although ATP hydrolysis by kinesin has many similarities to myosin biochemistry, there is at least one crucial difference: the two heads of kinesin are by no means independent, but act instead in a coordinated fashion, such that the binding and hydrolysis of ATP by one head promotes ADP release by its counterpart (Lohman et al. 1998references therein). This, and the finding that single-headed kinesin constructs do not sustain processive movement ( ,  and ), have lent support to the notion that dimeric kinesin moves “hand-over-hand,” advancing its heads in strict alternation. In this way, at least one head stays bound to the substrate at any given time, explaining how single kinesin molecules can move steadily against sustained loads approaching the stall force. An important corollary of this is that both heads must be capable of binding to a microtubule simultaneously, at least transiently.
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