The long-term objectives of this project are to identify and characterize the forces that underlie chromosome movement in meiosis and mitosis, including interactions of chromosomes with the spindle and microtubule dynamics involved in spindle assembly and function. The proposed studies focus on Ncd, a kinesin family microtubule motor protein in Drosophila. Ncd is a minus end-directed motor that plays an essential role in spindle assembly and function in meiosis and mitosis. The proposed studies focus on 1) the mechanism by which the 'neck', the region of the protein adjacent to the conserved motor domain, functions to determine motor directionality, 2) conformational changes in the motor that occur during motor function, and 3) the effects of minus-end motility and motor uncoupling on Ncd function in the cell.
The specific aims of the proposed studies are to: 1. Determine the mechanism of neck function in motor directionality. Functional tests of the neck in determining motor polarity will be performed by constructing mutant motors and analyzing polarity in vitro. 2. Identify regions of the motor involved in changes of conformation during motor function. Mutants that uncouple ATP hydrolysis from force generation or trap the motor in different states of ATP hydrolysis will be selected or designed, and tested in vitro to identify structural elements that move during motor function. 3. Determine the effect of minus-end polarity and motor uncoupling on Ncd function in vivo. Truncated mutants and motor uncoupling mutants will be introduced into Drosophila as gfp gene fusions to determine the effects of the mutated motors on Ncd function and dynamics in live cells. These studies address the molecular basis of force generation in the spindle and the role of microtubule motors in chromosome movement during cell division. Defective chromosome distribution causes aneuploidy and genetic abnormalities, and is associated with malignancies in humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Deatherage, James F
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Duke University
Schools of Medicine
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Kull, F Jon; Endow, Sharyn A (2013) Force generation by kinesin and myosin cytoskeletal motor proteins. J Cell Sci 126:9-19
Endow, Sharyn A; Nizami, Zehra F; Gerbi, Susan A (2013) A remarkable career in science-Joseph G. Gall. Chromosome Res 21:339-43
Liu, Hong-Lei; Hallen, Mark A; Endow, Sharyn A (2012) Altered nucleotide-microtubule coupling and increased mechanical output by a kinesin mutant. PLoS One 7:e47148
Liu, Hong-Lei; Pemble 4th, Charles W; Endow, Sharyn A (2012) Neck-motor interactions trigger rotation of the kinesin stalk. Sci Rep 2:236
Endow, Sharyn A; Hallen, Mark A (2011) Anastral spindle assembly and ýý-tubulin in Drosophila oocytes. BMC Cell Biol 12:1
Hallen, Mark A; Liang, Zhang-Yi; Endow, Sharyn A (2011) Two-state displacement by the kinesin-14 Ncd stalk. Biophys Chem 154:56-65
Endow, Sharyn A; Kull, F Jon; Liu, Honglei (2010) Kinesins at a glance. J Cell Sci 123:3420-4
Heuston, Elisabeth; Bronner, C Eric; Kull, F Jon et al. (2010) A kinesin motor in a force-producing conformation. BMC Struct Biol 10:19
Hallen, Mark A; Endow, Sharyn A (2009) Anastral spindle assembly: a mathematical model. Biophys J 97:2191-201
Liu, Honglei; Endow, Sharyn A (2009) Spindle function in yeast: a human motor to the rescue. Cell Cycle 8:3453-4

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