Project Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 7/1/17 → 11/30/23 |
Funding
- National Institute of General Medical Sciences: $286,607.00
- National Institute of General Medical Sciences: $286,465.00
- National Institute of General Medical Sciences: $286,536.00
- National Institute of General Medical Sciences: $317,041.00
- National Institute of General Medical Sciences: $286,676.00
- National Institute of General Medical Sciences: $285,068.00
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