Cooperative regulation of myosin-S1 binding to actin filaments by a continuous flexible Tm-Tn chain.
The regulation of striated muscle contraction involves cooperative interactions between actin filaments, myosin-S1 (S1), tropomyosin (Tm), troponin (Tn), and calcium. These interactions are modeled by treating overlapping tropomyosins as a continuous flexible chain (CFC), weakly confined by electrostatic interactions with actin. The CFC is displaced locally in opposite directions on the actin surface by the binding of either S1 or Troponin I (TnI) to actin. The apparent rate constants for myosin and TnI binding to and detachment from actin are then intrinsically coupled via the CFC model to the presence of neighboring bound S1s and TnIs. Monte Carlo simulations at prescribed values of the CFC stiffness, the CFC's degree of azimuthal confinement, and the angular displacements caused by the bound proteins were able to predict the stopped-flow transients of S1 binding to regulated F-actin. The transients collected over a large range of calcium concentrations could be well described by adjusting a single calcium-dependent parameter, the rate constant of TnI detachment from actin, k(-I). The resulting equilibrium constant K(B) ≡ 1/K(I) varied sigmoidally with the free calcium, increasing from 0.12 at low calcium (pCa >7) to 12 at high calcium (pCa <5.5) with a Hill coefficient of ~2.15. The similarity of the curves for excess-actin and excess-myosin data confirms their allosteric relationship. The spatially explicit calculations confirmed variable sizes for the cooperative units and clustering of bound myosins at low calcium concentrations. Moreover, inclusion of negative cooperativity between myosin units predicted the observed slowing of myosin binding at excess-myosin concentrations.
Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA. smijailo@gmail.com
Srboljub M
SM
Mijailovich
Oliver
O
Kayser-Herold
Xiaochuan
X
Li
Hugh
H
Griffiths
Michael A
MA
Geeves
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009218:Myosins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D055672:Static Electricity; D014335:Tropomyosin / Q000737:chemistry / Q000378:metabolism*; D014336:Troponin / Q000737:chemistry / Q000378:metabolism*
D014335:Tropomyosin; D014336:Troponin; D009218:Myosins; D002118:Calcium