EAGER: Biophysical Theory of Mitotic Spindle Length Instability and Self Assembly

University Of Colorado At Boulder, Boulder CO

Investigators

Abstract

NONTECHNICAL SUMMARY This award is made on an EAGER proposal, and it supports theoretical research and education on the biophysical theory of mitotic spindle length instability and self-assembly. The mitotic spindle is an important part of the cytoskeleton in eukaryotic cells. It is a self-assembled three-dimensional structure, primarily composed of tubes made from specific proteins, and it functions as a molecular machine that separates chromosomes during cell division. The ultimate goal of this research program is to provide an answer to the fundamental question: "How can the mitotic spindle, a non-equilibrium structure with constant molecular turnover i) self-assemble, and ii) maintain a fixed length." The PI intends to model the spindle length dynamics and self-assembly at multiple scales, ranging from nanometer to micron, bringing together ideas from statistical physics, molecular biophysics, structural, molecular, and cellular biology. The effort has a very substantial computational component involving a large-scale modeling framework. The PI intends to make the developed software freely available through an open-source license. TECHNICAL SUMMARY Cells self-organize and dynamically generate complex three-dimensional structures. Filament nucleation, polymerization, and interaction-driven rearrangement are regulated in space and time to construct a wide variety of assemblies. An important general question in the study of self-organized cytoskeletal structures is how to integrate molecular-level knowledge to predict higher-order aspects of assembly and organization. A prototypical self-assembled cytoskeletal structure is the mitotic spindle, a microtubule-based machine that segregates chromosomes during eukaryotic cell division. This project will create a physical theory of the fission yeast mitotic spindle that recapitulates spindle length stability/fluctuations and bipolar spindle assembly to address the fundamental question of how a non-equilibrium structure with constant molecular turnover can self-assemble and maintain a fixed length. This project has three components. The PI will first develop essential model ingredients including multiple species of motors/crosslinks, novel motor force-velocity relations, two-stage binding/unbinding of motors/crosslinks, and dynamic microtubules. Then the PI will determine the mechanisms underlying mitotic spindle length fluctuations and stabilization of spindle length through the integration of models that span from nanometer to micron scales. This component will lead to the development of a quantitative physical theory of dynamic stabilization of spindle length. Subsequently, the PI will determine the ingredients necessary for bipolar bundle assembly in a minimal model of the fission yeast mitotic spindle. This work will involve computational screens to find regions of model/parameter space associated with self-assembly of a stable spindle-like microtubule bundle and comparison to tomographic models. The effort has a very substantial computational component involving a large-scale modeling framework. The PI intends to make the developed software freely available through an open-source license.