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A more recent version of this article appeared on May 1, 2004
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Submitted on August 11, 2003
Revised on January 30, 2004
Accepted on January 30, 2004
1 Department of Biochemistry, Dartmouth Medical School, Hanover, N.H. 03755; Rippel Electron Microscope Facility, Dartmouth College, Hanover, N.H. 03755
* Corresponding author. E-mail address: duane.a.compton{at}dartmouth.edu.
We utilized computer simulation to understand the functional relationships between motor (dynein, HSET, & Eg5) and nonmotor (NuMA) proteins involved in microtubule aster organization. The simulation accurately predicted microtubule organization under all combinations of motor and nonmotor proteins, provided that microtubule cross-links at minus-ends were dynamic and dynein and HSET were restricted to cross-linking microtubules in parallel orientation only. A mechanistic model was derived from these data in which a combination of two aggregate properties, Net Minus end-directed Force and microtubule Cross-linking Orientation Bias, determine microtubule organization. This model utilizes motor and nonmotor proteins, accounts for motor antagonism, and predicts that alterations in microtubule Cross-linking Orientation Bias should compensate for imbalances in motor force during microtubule aster formation. We tested this prediction in the mammalian mitotic extract and, consistent with the model, found that increasing the contribution of microtubule cross-linking by NuMA compensated for the loss of Eg5 motor activity. Thus, this model proposes a precise mechanism of action of each noncentrosomal protein during microtubule aster organization, and suggests that microtubule organization in spindles involves both motile forces from motors and static forces from nonmotor cross-linking proteins.
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