A Helix Replacement Mechanism Directs Metavinculin Functions

Journal Article · Mon Oct 11 04:00:00 EDT 2010 · PLoS One

DOI:https://doi.org/10.1371/journal.pone.0010679· OSTI ID:1002794

Rangarajan, Erumbi S; Lee, Jun Hyuck; Yogesha, S D; Izard, Tina ^[1]

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1. Scripps

Cells require distinct adhesion complexes to form contacts with their neighbors or the extracellular matrix, and vinculin links these complexes to the actin cytoskeleton. 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. Moreover, patients with sporadic or familial mutations in the metavinculin-specific insert invariably develop fatal cardiomyopathies. 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 {Delta}Leu954 metavinculin deletion mutant. These structures reveal that an {alpha}-helix (H1{prime}) and extended coil of the metavinculin insert replace {alpha}-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. Further, biochemical analyses demonstrate that this helix replacement directs the distinct actin bundling and oligomerization properties of metavinculin. Finally, the cardiomyopathy associated {Delta}Leu954 and Arg975Trp metavinculin mutants reside on the replaced extended coil and the H1{prime} {alpha}-helix, respectively. Thus, a helix replacement mechanism directs metavinculin's unique functions.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002794
• Journal Information: PLoS One, Journal Name: PLoS One Journal Issue: (5) ; 2010 Vol. 5
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ACTIN
ADHESION
CRYSTAL STRUCTURE
HOMEOSTASIS
MUSCLES
MUTANTS
MUTATIONS
PATIENTS
RESIDUES
RESOLUTION