Kinesin-5: Cross-bridging mechanism to targeted clinical therapy

Abstract

Kinesin motor proteins comprise an ATPase superfamily that goes hand in hand with microtubules in every eukaryote. The mitotic kinesins, by virtue of their potential therapeutic role in cancerous cells, have been a major focus of research for the past 28 years since the discovery of the canonical Kinesin-1 heavy chain. Perhaps the simplest player in mitotic spindle assembly, Kinesin-5 (also known as Kif11, Eg5, or kinesin spindle protein, KSP) is a plus-end-directed motor localized to interpolar spindle microtubules and to the spindle poles. Comprised of a homotetramer complex, its function primarily is to slide anti-parallel microtubules apart from one another. Based on a multi-faceted analysis of this motor from numerous laboratories over the years, we have learned a great deal about the function of this motor at the atomic level for catalysis and as an integrated element of the cytoskeleton. These data have, in turn, informed the function of motile kinesins on the whole, as well as spearheaded integrative models of the mitotic apparatus in particular and regulation of the microtubule cytoskeleton in general. We review what is known about how this nanomotor works, its place inside the cytoskeleton of cells, and its small-molecule inhibitors that provide a toolbox for understanding motor function and for anticancer treatment in the clinic.

Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5

“…The region of the fulllength protein corresponding to the motor domain was chosen based on NCBI annotation. The Plasmodium amino acid sequences were analyzed along with Ͼ700 kinesin sequences from other taxa that were previously analyzed for kinesin evolutionary relationships (20). A multiple-sequence alignment and unrooted phylogeny were co-calculated using SATé (20,29).…”

“…The Plasmodium amino acid sequences were analyzed along with Ͼ700 kinesin sequences from other taxa that were previously analyzed for kinesin evolutionary relationships (20). A multiple-sequence alignment and unrooted phylogeny were co-calculated using SATé (20,29). Parameters used in the analysis were as follows: aligner, MAFFT; merger, OPAL; tree estimator, FASTTREE; maximum subproblem size, 200; decomposition, centroid; iteration limit, 20 after last improvement.…”

“…We note that in other eukaryotic systems, Kinesin-6, -7, -8, and -13 proteins have established roles in altering microtubule dynamics. Interestingly, there are no Plasmodium counterparts to the canonical Kinesin-1, which moves cellular cargo over vast distances, and only Kinesin-19 is hypothesized to be a processive kinesin (20).…”

“…As a microtubule cross-linking enzyme, the Kinesin-5 family is required for efficient cell division in all eukaryotes examined and is essential in nearly all (20). The essential Kinesin-5 subfamily mitotic motor proteins bear two important attributes that make them particularly tractable for drug discovery in high throughput screening experiments.…”

“…In addition, Kinesin-5 proteins house a druggable allosteric pocket that is conserved within the motor domain and yet variable in sequence across orthologs (20,24,25). Human Kinesin-5 inhibitors have been noted for their high degree of specificity for the target enzyme and lack of off-target effects (reviewed in Refs.…”