title: Force-induced activation of talin and its possible role in focal adhesion mechanotransduction.
abstract: 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.
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Seung E
authors.initials: SE
authors.lastname: Lee
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
authors.forename: Mohammad R K
authors.initials: MR
authors.lastname: Mofrad
mesh_terms: 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*
chemical_list: D016608:Talin