A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP (thus kinesins are ATPases). The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular cargo.
Conventional kinesin, a major microtubule-based motor protein responsible for anterograde axonal transport is a heterotetramer composed of two KHC and two KLC subunits. Intense KHC- and KLC1 immunoreactivity were also observed in scattered non-neuromelanin-laden small cells. In contrast, immunoreactivity for kinesin markers was markedly decreased in all Parkinson’s disease brains.
In this study, in vitro analysis showed that hGas7b binds directly to the microtubule and participates in the microtubule dynamics in the absence of any other MAPs. Conversely, high concentrations of hGas7b deform the microtubules, thereby interfering with the interaction between the microtubule and kinesin. These results suggested that an adequate concentration of hGas7b might be required for microtubule maintenance, but its excess can cause interruption of cell motility or intracellular trafficking.
Targeting mitotic kinesins is thus emerging as an attractive treatment modality in cancers that are refractory to taxane-based chemotherapies that act upon the mitotic spindle, since inhibition of kinesin motor proteins does not directly target microtubules. Moreover, mitotic kinesins are not expressed by neurons and are poor substrates for the P-glycoprotein efflux pump, which result in docetaxel's dose-limiting neurotoxicity and multidrug resistance. Hence, mitotic kinesin inhibition is hypothesized to induce mitosis-specific cell-cycle arrest that may complement current chemotherapeutic protocols with fewer side effects.
[The results from castration-resistant prostate cancer (CRPC) drug trials] also suggest that other mitosis-phase proteins may be potential targets for therapies treating this stage of [prostate cancer]. The mitotic centromere-associated kinesin (MCAK), whose gene expression was upregulated in multiple CRPC chemotherapy-resistant datasets, was selected for clinical and functional validation. MCAK protein expression was associated with clinical progression of prostate cancer, and its knockdown arrested the growth of prostate cancer cells.
Overexpression of MCAK is observed in coleorectal, gastric and breast cancer and correlates with a poor prognosis. MCAK expression causes increased cell proliferation and motility in cultured cells, whilst reduction of MCAK in a breast cancer cell line inhibits their growth. Chromosome instability, a common feature in many cancers, is increased in model systems by depletion of kinesin-13 or APC, causing long-lived kinetochore microtubule interactions.
As in mitosis, Bub1 also localized to the kinetochores of unaligned meiotic chromosomes in Drosophila, Xenopus and mouse oocytes. Bub1 is required for localization of Bub3 and Rec8 during meiosis I, suggesting that Bub1 kinase activity is essential for establishing proper kinetochore function. Bub1 mutation experiments lead to female-specific germ cell aneuploidy in mice, and chromosome missegregation and fragmentation are observed in Drosophila.
Kinesin-8s not only destabilize microtubules but also, in certain contexts, possess the ability to stabilize them. The importance of the microtubule destabilizing activity of kinesin-8s is underscored by the fact that loss of kinesin-8s generally leads to long cellular microtubules. The stabilizing effect of Kip3 on shrinking microtubules requires its microtubule- and tubulin-binding tail domain.
Kinesins also have a role in regulating microtubule formation at the most basic level of spatially directing the distribution of the tubulin subunits, especially in cellular protrusions such as axons and cilia. Axon formation is impaired by loss of CRMP-2, which binds tubulin heterodimers and promotes microtubule formation. The CRMP-2 tubulin complex is transported by Kinesin-1 along the axon to the growing distal end.
The possibility that different kinesins transport different axonal cargoes is supported by the observation that the predicted cargo binding regions of kinesin superfamily members have little sequence similarity. In
contrast, studies of conventional kinesin suggest that it can bind a variety of organelles in neurons and other cell types. Furthermore, experiments designed to disrupt kinesin function using antibodies and antisense oligonucleotides affect the movements of a wide range of organelles and proteins.
The kinesin superfamily of proteins share high sequence homology in their motor domains, which contain an ATP-binding catalytic core and microtubule-interacting surfaces. The motor domain forms an arrow-shaped structure that is built from a central β-sheet, flanked on each side by three α-helices. The arrow base lies flat on the microtubule lattice, with its tip pointed towards the plus-end.