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Dynamics of the C-Terminal Region of TnI in the Troponin Complex in Solution

Tharin M. A. Blumenschein ^*, Deborah B. Stone  , Robert J. Fletterick , Robert A. Mendelson  and Brian D. Sykes ^*

^* CIHR Group in Structure and Function and Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada; and Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, California 94143-2240

Correspondence: Address reprint requests to Brian D. Sykes, Tel: 780-492-5460; Fax: 780-492-0886; E-mail: Brian.Sykes{at}ualberta.ca.

The determination of crystal structures of the troponin complex (Takeda et al. 2003. Nature. 424:35–41; Vinogradova et al. 2005. Proc. Natl. Acad. Sci. USA. 102:5038–5043) has advanced knowledge of the regulation of muscle contraction at the molecular level. However, there are domains important for actin binding that are not visualized. We present evidence that the C-terminal region of troponin I (TnI residues 135–182) is flexible in solution and has no stable secondary structure. We use NMR spectroscopy to observe the backbone dynamics of skeletal [²H, ¹³C, ¹⁵N]-TnI in the troponin complex in the presence of Ca²⁺ or EGTA/Mg²⁺. Residues in this region give stronger signals than the remainder of TnI, and chemical shift index values indicate little secondary structure, suggesting a very flexible region. This is confirmed by NMR relaxation measurements. Unlike TnC and other regions of TnI in the complex, the C-terminal region of TnI is not affected by Ca²⁺ binding. Relaxation measurements and reduced spectral density analysis are consistent with the C-terminal region of TnI being a tethered domain connected to the rest of the troponin complex by a flexible linker, residues 137–146, followed by a collapsed region with at most nascent secondary structure.

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