Trends in Cell Biology
ReviewKinesin motors and disease
Section snippets
Kinesin structure, composition and nomenclature
The defining criterion for a kinesin is its ‘motor domain’, ≈320 residues in size, which binds and hydrolyses ATP (the energy source for movement) and binds to microtubules (the ‘tracks’ for movement; Fig. 1). The folding of the motor domain produces a core similar to that of other motors (e.g. the actin-dependent motor myosin) or signalling G-proteins [1]. The motor domain is usually coupled to additional domains with structural or regulatory roles. These in turn can attach to other cofactors,
Diseases caused by disruption of long-distance transport
Neurodegenerative diseases are often accompanied by aggregation of proteins in the cell body or cell processes, interruption of axonal transport, and eventually neuronal ‘dying-back’ or axonopathy. Examples are amyotrophic lateral sclerosis (ALS) with prominent neurofilament aggregates, or Alzheimer's disease with aggregates of the Aβ-peptide derived from amyloid precursor protein (APP) or of the microtubule-associated protein tau [17]. The ‘traffic jams’ observed in the dystrophic neurites are
Kinesin as a drug target
The cases discussed above involve traffic being obstructed because the motor was impaired or detached from its cargo, or the tracks were blocked, resulting in disease. But there is also the opposite situation where kinesin functions normally and the cell abuses this for a disease-causing process. This is the case in cancer where cell division is no longer properly regulated. Considering the number of kinesins involved in mitosis they should be natural targets for cytostatic drugs. This use of
Other disease-related roles of kinesins
Microtubule-dependent transport is involved in the intracellular transport of certain viruses, bacteria or parasites. This can take place at several levels, such as docking, and transport towards the nucleus or back to the cell membrane [37]. In the case of vaccinia virus, KIF5 is needed to transport the viral protein A36R, which interacts with the TPR domain of the light chains [38]. The interaction of retroviral Gag proteins with KIF4 is a prerequisite for viral capsid assembly [39]. The
Concluding remarks
There is as yet no clinically approved drug that is targeted specifically against kinesin, but a phase I clinical trial has just been announced by Cytokinetics (see www.cytokinetics.com). The examples mentioned above suggest several opportunities. The most obvious ones relate to the role of kinesin in mitosis, which could be exploited by kinesin inhibitors in cancer chemotherapy. The same strategy would apply to other diseases, for example arthritis, where the disease features pathological
Acknowledgements
We thank A. Marx for stimulating discussions and help with the composition of figures.
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