title: The crystal structure and biochemical characterization of Kif15: a bifunctional molecular motor involved in bipolar spindle formation and neuronal development.
abstract: Kinesins constitute a superfamily of microtubule-based motor proteins with important cellular functions ranging from intracellular transport to cell division. Some kinesin family members function during the mitotic phase of the eukaryotic cell cycle and are crucial for the successful progression of cell division. In the early stages of mitosis, during prometaphase, certain kinesins are required for the formation of the bipolar spindle, such as Eg5 and Kif15, which seem to possess partially overlapping functions. Because kinesins transform the chemical energy from ATP hydrolysis into mechanical work, inhibition of their function is a tractable approach for drug development. Drugs targeting Eg5 have shown promise as anticancer agents. Kif15 has recently come to the fore because it can substitute the functions of Eg5, and may itself have potential as a prospective drug target. Here, the initial biochemical, kinetic and structural characterization of Kif15 is reported and it is compared with the functionally related motor Eg5. Although Kif15 contains ADP in the catalytic site, its motor-domain structure was captured in the `ATP-like' configuration, with the neck linker docked to the catalytic core. The interaction of Kif15 with microtubules was also investigated and structural differences between these two motors were elucidated which indicate profound differences in their mode of action, in agreement with current models of microtubule cross-linking and sliding.
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland.
authors.forename: Marta
authors.initials: M
authors.lastname: Klejnot
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Falnikar
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland.
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Ulaganathan
authors.affiliation: Warwick Medical School, University of Warwick, Coventry CV4 7AL, England.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cross
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Baas
authors.affiliation: School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, England.
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D016547:Kinesins / Q000737:chemistry* / Q000378:metabolism*; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: C470243:KIF11 protein, human; C486567:KIF15 protein, human; D000244:Adenosine Diphosphate; D000251:Adenosine Triphosphatases; D016547:Kinesins; D008274:Magnesium
keywords: Eg5; Kif15; bipolar spindle formation; human kinesins; mitosis