The metavinculin tail domain directs constitutive interactions with raver1 and vinculin RNA.
Vinculin is a key regulator of the actin cytoskeleton attachment to the cell membrane at cellular adhesion sites, which is crucial for processes such as cell motility and migration, development, survival, and wound healing. Vinculin loss results in embryonic lethality, cardiovascular diseases, and cancer. Its tail domain, Vt, is crucial for vinculin activation and focal adhesion turnover and binds to the actin cytoskeleton and acidic phospholipids upon which it unfurls. The RNA binding protein raver1 regulates the assembly of focal adhesions transcriptionally by binding to vinculin. The muscle-specific splice form, metavinculin, is characterized by a 68-residue insert in the tail domain (MVt) and correlates with hereditary idiopathic dilated cardiomyopathy. Here, we report that metavinculin can bind to raver1 in its inactive state. Our crystal structure explains this permissivity, where an extended coil unique to MVt is unfurled in the MVtΔ954:raver1 complex structure. Our binding assays show that raver1 forms a ternary complex with MVt and vinculin mRNA. These findings suggest that the metavinculin:raver1:RNA complex is constitutively recruited to adhesion complexes.
Department of Cancer Biology, Cell Adhesion Laboratory, The Scripps Research Institute, FL 33458, USA.
Jun Hyuck
JH
Lee
Department of Cancer Biology, Cell Adhesion Laboratory, The Scripps Research Institute, FL 33458, USA.
Erumbi S
ES
Rangarajan
Global Phasing Ltd., Sheraton House, Castle Park, Cambridge CB3 0AX, UK.
Clemens
C
Vonrhein
Global Phasing Ltd., Sheraton House, Castle Park, Cambridge CB3 0AX, UK.
Gerard
G
Bricogne
Department of Cancer Biology, Cell Adhesion Laboratory, The Scripps Research Institute, FL 33458, USA. Electronic address: mkernick@scripps.edu.
Tina
T
Izard
D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D012261:Ribonucleoproteins; D016596:Vinculin / Q000737:chemistry* / Q000378:metabolism*
D002352:Carrier Proteins; D009687:Nuclear Proteins; C486705:RAVER1 protein, human; D012261:Ribonucleoproteins; C103334:metavinculin; D016596:Vinculin; D012313:RNA