Using nuclear magnetic resonance (NMR) spectroscopy and recombinant DNA techniques to model its three-dimensional solution structure, John Putkey, Ph.D., associate professor in the department of biochemistry & molecular biology at UT- Houston, in collaboration with Brian D. Sykes, Ph.D., professor of biochemistry at the University of Alberta, Edmonton, Canada, revealed elements of cardiac TnC which may help explain functional differences between cardiac and skeletal muscle contraction. Found only in heart muscle, cardiac TnC closely resembles skeletal TnC, one of a family of calcium-binding proteins which change shape as they relay biochemical signals which lead to muscle contraction. Now that the structure of cardiac TnC is known, researchers' ability to design clinically effective drugs will be significantly improved.
Dr. Putkey said: "A fundamental feature of the molecular mechanism of muscle regulation is a cyclic change in the three-dimensional conformation of the protein TnC as it binds and releases calcium. Troponin C can be conceptualized as a molecular switch: when calcium is bound, the muscle contractsDwhen calcium is released, the muscle relaxes. To fix or modify any machine one must know how it works. If that machine is a protein, then you need to know its three-dimensional structure. The structures of the cardiac and skeletal forms of TnC reveal profound and largely unexpected differences. These three-dimensional views provide valuable clues about how cardiac TnC works and how we may selectively modify its function."
Numerous studies have been conducted to identify drugs which increase cardiac TnC's affinity for calcium, thereby 'boosting' the action of heart muscle. These were based on the assumption that the drug- binding potential of cardiac TnC was similar to the skeletal form. The work of Putkey and Sykes will aid efforts to produce new therapies for heart attack patients who develop congestive heart failure - the condition in which insufficient blood is pumped throughout the body. Treatment with appropriate calcium sensitizing drugs may help counter the heart muscle impairment found in these patients.
The NMR spectroscopy was conducted in Dr. Sykes' Edmonton laboratory where much of the earlier work on skeletal muscle troponin C took place. Commenting on his association with the UT-Houston team, Dr. Sykes said: "This has been an excellent collaboration bringing together the different expertise of the Houston and Edmonton research teams. The structure of cardiac TnC has revealed some quite unexpected features, and will go a long way towards explaining both the differences between cardiac and skeletal muscle contraction and also, on a very molecular level, how calcium binding to regulatory proteins such as TnC is linked to their triggering function in many biological systems."
Note: The authors of 'NMR Structure of Cardiac Troponin C
Reveals an Unexpected Closed Regulatory Domain' are Samuel K.
Sia, Monica X. Li, Leo Spyracopoulos, Stéphanie M. Gagné, Wen
Liu, John A. Putkey and Brian D. Sykes*.
* Corresponding
Author.
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Journal
Journal of Biological Chemistry