University of Minnesota
School of Physics & Astronomy
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Elias Puchner

A conditional gating mechanism assures the integrity of the molecular force-sensor titin kinase
Stahl SW, Puchner EM, Alexandrovich A, Gautel M, and Gaub HE, Biophysical journal 101, 1978-86 (2011)

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As more and more recent investigations point out, force plays an important role in cellular regulation mechanisms. Biological responses to mechanical stress are often based on force-induced conformational changes of single molecules. The force sensor, titin kinase, is involved in a signaling complex that regulates protein turnover and transcriptional adaptation in striated muscle. The structural architecture of such a force sensor determines its response to force and must assure both activity and mechanical integrity, which are prerequisites for its function. Here, we use single-molecule force-clamp spectroscopy to show that titin kinase is organized in such a way that the regulatory domains have to unfold before secondary structure elements that determine the overall fold and catalytic function. The stepwise unfolding over many barriers with a topologically determined sequence assures that the protein can react to force by conformational changes while maintaining its structural integrity.