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Sharon L. Campbell

University of North Carolina, USA

Title: Role of metavinculin in actin reorganization and force transmission


The Campbell lab at the University of North Carolina studies Ras superfamily GTPases as well as cell adhesion proteins that regulate cellular growth and motility. Our research employs a combination of biochemical, biophysical and structural biology approaches to characterize protein-protein and protein-ligand interactions, elucidate structures and characterize novel mechanisms of regulation.  Our structural and mechanistic studies of tumor promoter and tumor suppressor proteins, have led to the identification of novel effector interactions and post-translational modifications that drive Ras-mediated tumorigenesis, as well delineation of interactions critical for paladin, paxillin, focal adhesion kinase and vinculin-mediated cell motility. 


Vinculin (Vcn) is an essential cytoskeletal protein that acts as a scaffold to link transmembrane receptors to actin filaments, thereby playing a crucial role in cell adhesion, motility, and force transmission between cells. While Vcn is ubiquitously expressed, metavinculin (MVcn), a larger isoform of Vcn, is selectively expressed in smooth and cardiac muscle cells. Similar to Vcn, MVcn can directly associate with actin and remodel the actin cytoskeleton. However, distinct from Vcn, MVcn contains an additional exon that encodes a 68-residue insert.  Point mutations in the 68-residue insert have been associated with altered actin organization and heart disease. MVcn expression is higher in muscle cells that require greater force transmission. Given these observations, we postulate that MVcn plays an important role in force generation and transmission through its interaction with the actin cytoskeleton. The tail domains of Vcn (Vt) and MVcn (MVt) directly bind filamentous (F) actin and we have recently obtained ~8 Angstrom Cryo-EM reconstructions of Vt and MVt in complex with F-actin.  While Vt and MVt associate with F-actin through similar binding interfaces, they differ in their ability to reorganize actin filaments. We find that wild-type (WT) MVcn tail domain (MVt) does not bundle actin filaments, but the cardiomyopathy-associated MVt mutants show differences in actin filament bundling in vitro. We are currently investigating how MVcn regulates actin organization in the presence of Vcn. While we have observed that WT MVt inhibits Vt-mediated actin bundling, the disease-associated MVt mutants fail to inhibit Vt-mediated actin bundling via negative-stain EM. We have additionally succeeded in expressing MVcn in Vcn null mouse embryonic fibroblasts (MEF) and observed that MVcn localizes to focal adhesions, similar to Vcn. Results from these studies will provide the groundwork for how MVcn disease mutants contribute to associated cardiomyopathies.