The Mechanism of Thin Filament Regulation: Models in Conflict?

In a recent article in this journal, Heeley and colleagues (Heeley, White, and Taylor 2019 J Gen Physiol 151, 628-634) reopened the debate about 2 vs 3 state models of thin filament regulation. The authors review their work, which measures the rate constant of Pi release from myosin.ADP.Pi activated by actin or thin filaments under a variety of conditions. They conclude that their data can be described by a 2-state model and raise doubts about the generally accepted 3-state model as originally formulated by McKillop and Geeves (Biophysical Journal 65: 693–701, 1993). However, in the following article, we follow Plato’s dictum that “twice and thrice over, as they say, good it is to repeat and review what is good”. We have therefore reviewed the evidence for the 3- and 2-state models and present our view that the evidence is overwhelmingly in favor of three structural states of the thin filament, which regulate access of myosin to its binding sites on actin and, hence, muscle contractility.