Grant (PPG) will create a collaborative environment to coordinate research on centrosome structure, mechanics, homeostasis and function. Six investigators will study the Saccharomyces cerevisiae centrosome as a model microtubule-organizing center (MTOC) analogous to the vertebrate centrosome, which shares key homologous components and regulators. A centrosome/SPB is the primary microtubule-organizing center of the cell and is critical for bipolar spindle assembly and accurate mitotic chromosome segregation. Centrosome duplication is an essential cell cycle event being the first step in spindle formation; defects in duplication or function lead to genomic instability and cellular transformation. Accurate chromosome segregation depends on both proper regulation of spindle assembly and precise connections between spindle microtubules and chromosomes. The PPG is focused specifically on 10 core SPB components that form the lattice and microtubule nucleation sites including the y-tubulin complexes. These proteins act similarly to the pericentriolar material of vertebrate centrosomes, which is crucial for microtubule nucleation and organization, but poorly understood. We propose to elucidate the molecular architecture of the yeast centrosome and to probe the mechanisms, by which it is assembled, maintained and functions in nucleating microtubules. A multidisciplinary approach examining different aspects of the problem will be coordinated to include: determining how the structure and mechanics of the y-tubulin complex and associated proteins collaborate to accomplish microtubule nucleation; investigating how core SPB components are assembled and how they recruit ?-tubulin complexes; identifying the critical intrinsic and extrinsic factors for maintaining homeostasis of this dynamic organelle; solving the atomic structure of SPB components and complexes, and working toward an integrated structural model of the entire SPB core. This PPG builds on existing collaborations between David Agard (UCSF) and Trisha Davis (U. Washington) on g-tubulin complexes, and Ivan Rayment (U. Wisconsin) and Mark Winey (U. Colorado) on core SPB components. These four groups will work together on the 10 proteins. Their projects will profit from structural modeling of the SPB (Andrej Sali, UCSF) and quantifying the mechanical properties of the SPB using biophysical techniques (Chip Asbury, U. Washington). There is tremendous potential to produce an unprecedented molecular description of a centrosome revealing mechanisms of assembly, stability and function. This work will serve as a model for future analysis of the much more complex human centrosome.

Public Health Relevance

The goal of this project is to understand the structure and function of centrosomes. Centrosomes are important for correct chromosome movement within cells. Centrosome defects can lead to developmental delays resulting from chromosomal abnormalities and disease states such as cancer and neurological disorders. We are interested in learning how centrosomes normally function so that eventually we can understand the underlying molecular deficiency when problems arise.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1)
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Gindhart, Joseph G
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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