S. S. Lehrer
Boston Biomedical Research Institute, Boston MA 02114.
Evidence has been accumulating for the importance of cooperative effects in the regulation and generation of muscle contraction. Beginning with studies in A. Weber's laboratory (Bremel et al., 1972 CSH, 37, 267), cooperative effects of myosin binding to actin in the presence of tropomyosin and tropomyosin-troponin (Tm-Tn) have been characterized in several laboratories. Yet the roles of the various components in regulation has not been clear. This is due to the different approaches used and various states of the actin-Tm-Tn thin filament (Lehrer, 1994 JMRCM, 15, 232). To provide a simple framework to help understand how this system functions, I have used published and new data to see if the muscle thin filament functions as a classical MWC cooperative/allosteric system (Monod et al., 1965 JMB, 12, 88) analogous to hemoglobin (Hb) and aspartate transcarbamylase (ATCase). Here the basic cooperative/allosteric system is Tm-actin which exists in two activity states off/on, having catalytic subunits (actin), regulatory subunits (Tm), substrate (S1-ATP), allosteric activators (Tn + Ca2+, S1-ADP) and inhibitors (Tn - Ca2+, troponin I). There are three interesting contrasts with the classical globular systems: 1) the substrate, allosteric inhibitors and activators are proteins rather than small molecules; 2) the physiological activating ligand, i.e., the ligand that binds cooperatively to actin-Tm , is the product of the enzymatic reaction, S1-ADP, rather than the substrate, S1-ATP; 3) the average number of subunits switched-on by the binding of an activating ligand to one subunit, the cooperative unit size n, is related to the number of catalytic subunits in globular systems; i.e., 4 and 6, for Hb and ATCase, respectively. For a continuous filamentous system such as actin-Tm n can be greater than the structural unit size of actin-Tm. The implication of these differences will be discussed.
Supported by NIH 22461 and AR 41637.