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* Theoretical and Computational Biophysics Department, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; and Cardiovascular Research Division and The Randall Division, King's College London, London SE1 1UL, Great Britain
Correspondence: Address reprint requests to Helmut Grubmüller, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Tel.: 49-551-201-2301; Fax: 49-551-201-2302; E-mail: hgrubmu{at}gwdg.de.
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 ß-sheets as the primary unfolding steps. The low force resistance of the C-terminal relative to the N-terminal ß-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.
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