title: Mechanically induced titin kinase activation studied by force-probe molecular dynamics simulations.
abstract: The conversion of mechanical stress into a biochemical signal in a muscle cell requires a force sensor. Titin kinase, the catalytic domain of the elastic muscle protein titin, has been suggested as a candidate. Its activation requires major conformational changes resulting in the exposure of its active site. Here, force-probe molecular dynamics simulations were used to obtain insight into the tension-induced activation mechanism. We find evidence for a sequential mechanically induced opening of the catalytic site without complete domain unfolding. Our results suggest the rupture of two terminal beta-sheets as the primary unfolding steps. The low force resistance of the C-terminal relative to the N-terminal beta-sheet is attributed to their different geometry. A subsequent rearrangement of the autoinhibitory tail is seen to lead to the exposure of the active site, as is required for titin kinase activity. These results support the hypothesis of titin kinase as a force sensor.
authors.affiliation: Theoretical and Computational Biophysics Department, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D003198:Computer Simulation; D064211:Connectin; D004548:Elasticity; D004789:Enzyme Activation; D019563:Mechanics; D008956:Models, Chemical; D008958:Models, Molecular; D009124:Muscle Proteins / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure*; D010812:Physical Stimulation / Q000379:methods; D011487:Protein Conformation; D011494:Protein Kinases / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure*; D013314:Stress, Mechanical; D013329:Structure-Activity Relationship
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases