275459 Simulations of Microtubule Forces Derived From Cytoskeletal-Bound Motors

Monday, October 29, 2012: 5:31 PM
411 (Convention Center )
Anthony J.C. Ladd1, Gaurav Misra2,3, Jun Wu1, Robert J. Russell1, Nandini Shekhar1, Tanmay Lele1 and Richard Dickinson1, (1)Department of Chemical Engineering, University of Florida, Gainesville, FL, (2)Laboratory for Rehabilitation Neuroscience, University of Florida, (3)Department of Bioengineering, Stanford University, Stanford, CA

Microtubules are key components of force transmission in cells, and play a role in cell locomotion, transport, and mitosis. Experiments in Lele's group[1] have shown that microtubules severed by laser ablation do not straighten, as would be expected from the large bending moments along their lengths. Instead, segments near newly created minus ends typically increased in curvature following severing, while segments near new microtubule plus ends depolymerize before any observable change in shape. However, in dynein-inhibited cells, segments near the cut straightened rapidly following severing. These observations suggest that microtubules are subject to significant tangential forces, and that lateral motion of the microtubule is opposed by a large effective friction rather than elastic forces. To help interpret the experimental results we have developed a numerical model for intracellular microtubule mechanics, accounting for dynein-generated forces on the microtubules.

At the length scales of mammalian cells, microtubules behave as semi-flexible filaments and can be coarse-grained using the Kirchoff theory for elastic rods. We have supplemented the Kirchoff model[2] with the stochastic growth and collapse of microtubules[3] (the dynamic instability), and by a model for dynein generated forces[1]. Numerical simulations of the buckling of a single microtubule can explain both the enhanced buckling at the minus end of a severed microtubule and the apparently frozen shape of the plus end. I will present simulations of the dynamics of individual microtubules that explain how motor forces result in the localization of short-wavelength buckles near the cell periphery. Our results suggests that microtubule shapes in vivo reflect a dynamic force balance, where bending moments are opposed by dynein-motor forces, including an effective friction from the stochastic binding and unbinding of the motors. Simulations of the motion of the centrosome are consistent with a mechanism for centrosome centering driven by pulling forces exerted by dynein motors. The simulations also explain how tension on the centrosome can be reconciled with buckled filaments near the cell periphery. I will present results of ongoing calculations that aim to discover if discrete distributions of molecular motors can explain experimentally observed fluctuations in filament shapes.

[1] J. Wu et al., Molec. Biol. Cell, 22:4834-4841, 2011.

[2] A. J. C. Ladd and G. Misra, J. Chem. Phys. 130:124909, 2009.

[3] T. Mitchison and M. Kirschner Nature 312: 237-42, 1984.

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