The Molecular Mechanism Regulating Muscle Contraction Partly Understood

Nathalie Alauzet (Analyst, ATIP)

The Institute of Physical and Chemical Research (RIKEN) and the Japan Science and Technology Corporation (JST) succeeded for the first time in the world in determining the structure of troponin. Troponin is a human cardiac protein which plays a key role in the regulation of muscle contraction and in determining the molecular mechanism related to it.

The contraction of skeletal and cardiac muscles is regulated by changes in the concentration of intracellular calcium ions, and troponin is essential in this Ca(2+) regulation. It interacts with tropomyosin to control the attachment of crossbridges to actin.

It is thus necessary to know the detailed structure of troponin to understand the mechanism of Ca(2+) regulation. In this study by RIKEN and JST the solid structure of the core domain, which is necessary for the function of human heart muscle, was determined in its Ca2+-saturated form. Obtaining a good crystal proved to be very difficult, and it took 13 years to perform it successfully. From the structure obtained, it became clear that the troponin molecule undergoes major conformational change through the binding of calcium ions. Moreover, it is suggested that those conformational changes are transmitted to the other heart proteins which are bound to troponin, tropomyosin, and actin. The core domain of troponin is composed of subdomains, which are flexibly connected to one another. It seems that this soft connection allows daramtic changes in the binding of troponin to other proteins.

The elucidation of the crystal structure of troponin is expected to bring further progress to the research on the mechanisms of calcium regulation in muscle contraction. This discovery will also accelerate other areas of biomedical research, such as: the development of new diagnostic methods, improved heart failure treatments, and the understanding of hereditary heart diseases.

The research involved the research team of Yuichiro Maeda, including K. Maeda, A. Yamashita and S. Takeda, from the Laboratory for Structural Biochemistry, RIKEN Harima Institute at Spring-8 (S. Takeda is presently Head of the Department of cardiac Physiology, National Cardiovascular center Research Institute).

The research was supported by RIKEN and JST through the PRESTO programme, and by the Special Coordination Funds from MEXT. Details about this research have been published in Nature (July 3rd issue).