Mechanically induced titin kinase activation studied by force probe molecular dynamics simulations

¹ Max-Planck-Institute for Biophysical Chemistry
² Drug Discovery and Design Center, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
³ King's College London
⁴ Max-Planck-Institut für Biophysikalische Chemie

^* To whom correspondence should be addressed. E-mail: hgrubmu{at}gwdg.de.

Submitted on September 3, 2004
Revised on October 6, 2004
Accepted on 7 October 2004

	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 auto inhibitory 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.

Key Words: Titin kinase activation, beta sheet geometry, enforced unfolding, force probe simulation, force sensor, molecular dynamics

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