Force-induced activation of talin and its possible role in focal adhesion mechanotransduction.
It is now well established that cells can sense mechanical force, but the mechanisms by which force is transduced into a biochemical signal remain poorly understood. One example is the recruitment of vinculin to reinforce initial contacts between a cell and the extracellular matrix (ECM) due to tensile force. Talin, an essential linking protein in an initial contact, contains at least one vinculin-binding site (VBS) that is cryptic and inactive in the native state. The N-terminal five-helix bundle of talin rod is a stable structure with a known cryptic VBS1. The perturbation of this stable structure through elevated temperature or destabilizing mutation activates vinculin binding. Although the disruption of this subdomain by transmitted mechanical force is a potential cue for the force-induced focal adhesion strengthening, the molecular basis for this mechanism remains elusive. Here, molecular dynamics (MD) is employed to demonstrate a force-induced conformational change that exposes the cryptic vinculin-binding residues of VBS1 to solvent under applied force along a realistic pulling direction. VBS1 undergoes a rotation of 62.0 +/- 9.5 degrees relative to its native state as its vinculin-binding residues are released from the tight hydrophobic core. Charged and polar residues on the VBS1 surface are the site of force transmission that strongly interact with an adjacent alpha-helix, and in effect, apply torque to the VBS1 to cause its rotation. Activation was observed with mean force of 13.2 +/-8.0 pN during constant velocity simulation and with steady force greater than 18.0 pN.
Lee
Seung E
SE
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Kamm
Roger D
RD
Mofrad
Mohammad R K
MR
D019943:Amino Acid Substitution / Q000235:genetics; D022001:Focal Adhesions / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological; D008958:Models, Molecular; D016608:Talin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016608:Talin