A conditional gating mechanism assures the integrity of the molecular force-sensor titin kinase

Stefan W. Stahl, Elias M. Puchner, Alexander Alexandrovich, Mathias Gautel, Hermann E. Gaub

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1978-1986
Number of pages9
JournalBiophysical journal
Volume101
Issue number8
DOIs
StatePublished - Oct 19 2011

Bibliographical note

Funding Information:
M.G. and A.A. gratefully acknowledge the generous support by the British Heart Foundation and the Medical Research Council. M.G. holds the British Heart Foundation Chair of Molecular Cardiology. E.M.P. is supported by the Deutsche Forschungsgemeinschaft. This work was supported by the Nanosystems Initiative Munich, the Volkswagenstiftung, and the Deutsche Forschungsgemeinschaft Grant SFB 863.

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