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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.