Mechanisms Regulating Actin Cytoskeleton Dynamics

Brandeis University, Waltham MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Our long-term goal is to understand how cell architecture and function are regulated by dynamic rearrangements of the actin cytoskeleton. Remodeling of actin networks in response to intracellular and extracellular signals is essential for fundamental biological processes, including cell division, cell migration, cell morphogenesis, intracellular transport, and endocytosis. The specific focus of our lab's research is to determine how multiple actin-associated proteins with diverse activities function in concert to elicit changes in actin dynamics and organization. We are addressing open questions about the mechanisms and functions of these proteins using budding yeast Saccharomyces cerevisiae as a model organism for our in vivo studies. We take a multi-disciplinary approach to solving these problems: biochemical, genetic, structural, and cell biological, combined with microscopic imaging of individual actin filament dynamics in real time in vitro and electron microscopy and single particle analysis to solve protein structures. In this proposal, we seek to understand how three highly conserved proteins, coronin, Arp2/3 complex, and cofilin, function together to control the formation and rapid disassembly of actin filaments. Our work during the last funding period identified two novel cellular functions for yeast coronin in regulating actin dynamics, one Arp2/3 complex-dependent and one cofilin-dependent. Our goal is to use this knowledge as a starting point to arrive at a more complete understanding of these new mechanisms and functions. The Specific Aims are: (1) How does coronin toggle between oligomerizing to bundle F-actin and associating with Arp2/3 complex to regulate actin assembly? (2) How does coronin affect Arp2/3 complex-dependent actin nucleation and branching? (3) How does coronin amplify the effects of cofilin in promoting actin filament disassembly? Defining the molecular basis of these cellular events is critical not only for understanding normal human physiology, but also for determining how defects in the specific genes that control these processes lead to disease states arising from mis-regulation of cytoskeletal architecture, including cancer, birth defects, heart disease, and neurodegenerative disorders. [unreadable] [unreadable] [unreadable]