Professor Margaret Titus

CBS Genetics, Cell Bio, Dev
College of Biological Sciences
Twin Cities
Project Title: 
Molecular Evolution of MyTH-FERM Myosins

Cell motility, the movement of cells through their environment, is of critical importance in immune function, the development of specialized tissues, and (when dysregulated) cancer cell invasion and metastasis. This group studies myosins, a family of motor proteins with deep evolutionary roots that control cell shape, motility, and migration in both animals and Dictyostelium (Dicty), a social amoeba. Dicty is a unicellular organism that feeds on soil bacteria and develops into a multicellular aggregate, and is a model for cell motility and migration. These researchers have identified two MyTH4-FERM (MF) myosins in Dicty. MF myosins contain both a motor and a binding module, the MyTH4-FERM domain, allowing the motor to generate force across the cytoskeleton and receptors at the cell membrane. MF myosins play roles in formation of large actin-filament structures including microvilli that stabilize the gut lining (Myosin 7b), stereocilia essential for hearing (Myosins 7a and 15), and filopodia that aid migration of epithelial cells and neurons (Myosin 10).

Research in the Titus laboratory uses cell biology and genetics to understand biological function of MF myosins, combined with computational phylogenetics to trace the evolution of the MF myosin family. They have shown that Dicty Myosin 7 generates filopodia in concert with the actin filament bundling protein VASP, in a mechanism strikingly reminiscent of Myosin 10 and VASP in humans. The similar functions of these two myosins suggests a shared ancestral function may have been conserved extensive divergence of animal and amoebozoan myosins. Phylogenetic analysis allows for the use of the MF myosins to show how ancestral functions may be either conserved or lost as new functions emerge in a gene family. The researchers also perform structural analysis through crystallization of MF domains to produce atomic structures, which have revealed novel binding interfaces on Dicty Myosin 7. In human Myosin 7a and 7b, they have solved the structure of the tripartite complex that allows these motors to provide mechanical stability in stereocilia and microvilli, respectively. The combination of computational phylogenetic and structural biology approaches provides unique insight into how novel mechanical functions arose in myosin motor proteins.

Project Investigators

Ashley Arthur
Karl Petersen
Professor Margaret Titus
 
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