Molecular mechanisms of bundled actin structure assembly by formins

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PROJECT SUMMARY The goal of this research is to understand how formins shape the architecture and dynamics of the actin cytoskeleton. Formins are a uniquely versatile family of actin regulatory proteins that stimulate both filament nucleation and elongation. Actin filaments assembled by formins are incorporated into a diverse set of higher- order structures that support essential cellular functions, including migration, division, and transport. Mammals express 15 formin isoforms, each of which possesses unique actin assembly properties and plays a specific role in cells. Consistent with this specialization, mutations in individual formin genes are linked to a broad range of diseases and pathologies, including neurological disorders, kidney disease, microcephaly, cardiomyopathy, and several cancers. However, despite their foundational roles as regulators of actin assembly, it is unknown how the polymerization activity of each formin isoform is tailored for the assembly of a specific actin structure. To bridge this gap in understanding, our goal is to establish how the broad range of formin activities influences actin network physiology and dynamics. Our central hypothesis is that formins direct the assembly and specialization of higher-order actin structures by generating binding sites for bundling and severing proteins at isoform-specific rates. We will use a combination of biophysical and cell biological approaches to test this hypothesis by pursuing three specific aims: (1) to elucidate the mechanism that underpins the adaptable polymerization activities of formins, (2) to investigate the effects of formin-mediated elongation on actin filament bundling, and (3) to assess the interdependent contributions of filament nucleation, elongation, and turnover to actin structure dynamics. Our work will establish at a molecular level how formins dynamically regulate the construction, specialization, and function of cytoskeletal structures that are essential for cellular viability and human development. In light of the diversity of formin isoforms, our results will generate fundamental insights into the molecular and temporal regulation of a large number of cellular processes. This will inform and guide our understanding of the molecular pathologies underlying a diverse set of human diseases linked to mutations in formin genes.