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Physicochemical changes in phosphorylase kinase associated with its activation

Phosphorylase kinase (PhK) regulates glycogenolysis through its Ca2+‐dependent phosphorylation and activation of glycogen phosphorylase. The activity of PhK increases dramatically as the pH is raised from 6.8 to 8.2 (denoted as ↑pH), but Ca2+ dependence is retained. Little is known about the structural changes associated with PhK's activation by ↑pH and Ca2+, but activation by both mechanisms is mediated through regulatory subunits of the (αβγδ)4 PhK complex. In this study, changes in the structure of PhK induced by ↑pH and Ca2+ were investigated using second derivative UV absorption, synchronous fluorescence, circular dichroism spectroscopy, and zeta potential analyses. The joint effects of Ca2+ and ↑pH on the physicochemical properties of PhK were found to be interdependent, with their effects showing a strong inflection point at pH ∼7.6. Comparing the properties of the conformers of PhK present under the condition where it would be least active (pH 6.8 − Ca2+) versus that where it would be most active (pH 8.2 + Ca2+), the joint activation by ↑pH and Ca2+ is characterized by a relatively large increase in the content of sheet structure, a decrease in interactions between helix and sheet structures, and a dramatically less negative electrostatic surface charge. A model is presented that accounts for the interdependent activating effects of ↑pH and Ca2+ in terms of the overall physicochemical properties of the four PhK conformers described herein, and published data corroborating the transitions between these conformers are tabulated.