The Structural Basis of Actin Organization by Vinculin and Metavinculin.
Vinculin is an essential adhesion protein that links membrane-bound integrin and cadherin receptors through their intracellular binding partners to filamentous actin, facilitating mechanotransduction. Here we present an 8.5-Å-resolution cryo-electron microscopy reconstruction and pseudo-atomic model of the vinculin tail (Vt) domain bound to F-actin. Upon actin engagement, the N-terminal "strap" and helix 1 are displaced from the Vt helical bundle to mediate actin bundling. We find that an analogous conformational change also occurs in the H1' helix of the tail domain of metavinculin (MVt) upon actin binding, a muscle-specific splice isoform that suppresses actin bundling by Vt. These data support a model in which metavinculin tunes the actin bundling activity of vinculin in a tissue-specific manner, providing a mechanistic framework for understanding metavinculin mutations associated with hereditary cardiomyopathies.
Laboratory of Macromolecular Interactions, Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Laura Y
LY
Kim
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Peter M
PM
Thompson
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Hyunna T
HT
Lee
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mihir
M
Pershad
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sharon L
SL
Campbell
Laboratory of Macromolecular Interactions, Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: alushing@mail.nih.gov.
Gregory M
GM
Alushin
D000199:Actins / Q000737:chemistry* / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D016596:Vinculin / Q000737:chemistry* / Q000378:metabolism*
D000199:Actins; D016596:Vinculin
adhesion; cell motility; cryo-EM; cytoskeleton; mechanobiology