dynamic light scattering at the scripps research institute

Metavinculin levels are tightly controlled by signals regulating muscle function, where for example changes in mechanical load induce marked increases in levels of metavinculin protein. Īll muscle cell types selectively express an alternatively spliced isoform of vinculin, coined metavinculin, which harbors a 68-residue insert positioned between α-helices H1 and H2 of the Vt domain. Accordingly, in the mouse vinculin loss leads to defects in adhesion complexes that compromise embryonic cardiac development and vinculin +/− mice develop dilated cardiomyopathy. These links are provided in part by vinculin, a highly conserved and structurally dynamic protein that stabilizes adhesions complexes and which binds to actin through the agency of its five-helix bundle tail (Vt) domain. At one level this relies on proper links of the actin network to cadherin receptor-mediated cell-cell adherens junctions, to integrin receptor-directed focal adhesions, and to intercalated discs that are required for muscle cell function and that orchestrate coordinated movement. The morphology and functions of specialized cells within tissues such as muscle requires unique organization of the actin cytoskeleton, but how this is controlled is poorly understood. Thus, a helix replacement mechanism directs metavinculin's unique functions. Finally, the cardiomyopathy associated ΔLeu954 and Arg975Trp metavinculin mutants reside on the replaced extended coil and the H1′ α-helix, respectively.

Further, biochemical analyses demonstrate that this helix replacement directs the distinct actin bundling and oligomerization properties of metavinculin. These structures reveal that an α-helix (H1′) and extended coil of the metavinculin insert replace α-helix H1 and its preceding extended coil found in the N-terminal region of the vinculin tail domain to form a new five-helix bundle tail domain. Here we report the high resolution crystal structure of the metavinculin tail domain, as well as the crystal structures of full-length human native metavinculin (1,134 residues) and of the full-length cardiomyopathy-associated ΔLeu954 metavinculin deletion mutant. Moreover, patients with sporadic or familial mutations in the metavinculin-specific insert invariably develop fatal cardiomyopathies. Metavinculin, an isoform of vinculin that harbors a unique 68-residue insert in its tail domain, has distinct actin bundling and oligomerization properties and plays essential roles in muscle development and homeostasis. Cells require distinct adhesion complexes to form contacts with their neighbors or the extracellular matrix, and vinculin links these complexes to the actin cytoskeleton.

Dynamic light scattering at the scripps research institute