Wednesday, April 2, 2025
4/2/2025
Structural and Biochemical Mechanisms of Microtubule Dynamics and Regulation - Microtubules (MTs) are essential dynamic polymers required for chromosome segregation and intracellular organization, and are the direct targets of anti-cancer chemotherapeutics like taxol and the Vinca alkaloids. The dynamic properties of MTs are central to their function, and they derive from the structural and biochemical properties of individual tubulin subunits and how they interact within the MT lattice. It is increasingly appreciated that tubulin subunits adopt distinct conformations as part of the GTPase-dependent polymerization dynamics, and that regulatory proteins selectively recognize subsets of these conformations to control MT elongation, stability, and switching. Research in the laboratory uses a combination of structure (X-ray crystallography and cryo-EM), quantitative biochemistry, time-lapse observation of microtubule dynamics, and computational simulations. Mechanism-specific, site-directed tubulin mutants are used to integrate the different sources of information and also to test hypotheses and create new tools. In the present proposal, we will focus on complementary lines of investigation to provide new insights into the physical origins and regulatory mechanism of MT dynamics. We will reveal the allosteric logic of the tubulin conformation cycle and provide fresh biochemical insight by studying newly identified mutations linked to microtubule stability. We will use single-molecule observations of tubulins interacting with microtubule ends to define and quantify biochemical mechanisms and generate new hypotheses. We will reveal how relatively divergent α-tubulin isotypes and/or primitive tubulins alter MT dynamics and structure. Finally, we will define how specialized TOG domains recognize tubulin and/or MTs to regulate MT dynamics. This work will advance understanding of fundamental mechanisms of MT dynamics, recognition, and regulation, and it will begin to reveal critical points of allosteric connection within αβ-tubulin. Longer-term goal of this research are: to build a quantitative molecular understanding of how allostery and the tubulin conformation cycle dictate MT stability, dynamics, and mechanochemistry, to define mechanisms by which regulatory factors recognize tubulin and control MT dynamics, and to place this knowledge more firmly into a functional context.
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