Public Health Relevance

R01 GM071596A1 - PROGRAM NARRATIVE Cells require distinct adhesion complexes at their cell surface to form contacts with their neighbors or with the extracellular environment, and the protein vinculin plays essential roles in linking these adhesion complexes to the actin cytoskeleton, and in directing the cell migration machinery. The formation of these links requires that vinculin transition from its closed, inactive conformation to its activated state, and the studies supported by R01 GM071596 defined the structure of inactive and activated vinculin, and revealed its mechanism of activation. However, essentially nothing is known regarding the interactions of activated vinculin with its binding partners in the cell, and our new studies in this revised competitive renewal application of R01 GM071596 will define the structure and function of vinculin in complex with three of its partners that play essential roles in adhesion complexes, in cell migration, and in the localized production of components of adhesion junctions. Finally, we will also define the structure and function of metavinculin, an isoform of vinculin that plays essential roles in the formation and function of muscle tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071596-08
Application #
8027759
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Flicker, Paula F
Project Start
2004-08-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
8
Fiscal Year
2011
Total Cost
$403,257
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Rangarajan, Erumbi S; Izard, Tina (2013) Dimer asymmetry defines α-catenin interactions. Nat Struct Mol Biol 20:188-93
Lee, Jun Hyuck; Rangarajan, Erumbi S; Vonrhein, Clemens et al. (2012) The metavinculin tail domain directs constitutive interactions with raver1 and vinculin RNA. J Mol Biol 422:697-704
Rangarajan, Erumbi S; Lee, Jun Hyuck; Izard, Tina (2011) Apo raver1 structure reveals distinct RRM domain orientations. Protein Sci :
Pilati, Camilla; Amessou, Mohamed; Bihl, Michel P et al. (2011) Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med 208:1359-66
Rangarajan, Erumbi S; Izard, Tina (2010) Improving the diffraction of full-length human selenomethionyl metavinculin crystals by streak-seeding. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:1617-20
Rangarajan, Erumbi S; Lee, Jun Hyuck; Yogesha, S D et al. (2010) A helix replacement mechanism directs metavinculin functions. PLoS One 5:e10679
Rebouissou, Sandra; Amessou, Mohamed; Couchy, Gabrielle et al. (2009) Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457:200-4
Lee, Jun Hyuck; Rangarajan, Erumbi S; Yogesha, S D et al. (2009) Raver1 interactions with vinculin and RNA suggest a feed-forward pathway in directing mRNA to focal adhesions. Structure 17:833-42
Nhieu, Guy Tran Van; Izard, Tina (2007) Vinculin binding in its closed conformation by a helix addition mechanism. EMBO J 26:4588-96
St-Jean, Miguel; Izard, Tina; Sygusch, Jurgen (2007) A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions with Wiskott-Aldrich syndrome protein. J Biol Chem 282:14309-15

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