The enzyme CaMKII plays a central role in translating fluctuations of cellular calcium levels into signals that mediate many biological processes – from heart rhythms to learning and memory. The enzyme has three main pieces, or domains, which change shape (conformation) to activate the enzyme.
A more detailed understanding of this shape-shifting is necessary to design therapies targeting the enzyme.
Using molecular “spies” (spin labels) to visualize these changes, Hassane Mchaourab, Roger Colbran, and colleagues found that the business end (the “kinase” domain) is kept in an inhibited state by the conformational qualities of another domain (the regulatory domain). Binding of calmodulin – a calcium-binding protein that “senses” calcium fluctuations – to the regulatory domain induces structural changes that activate the kinase domain and enhance the enzyme’s interaction with calmodulin.
The findings, published recently in The EMBO Journal, offer a dynamic picture of CaMKII activation which can potentially inform development of new therapeutic strategies for neurological, psychiatric or cardiac diseases.
The research was supported by the Vanderbilt University IDEAS program, a trans-institutional program to foster collaborations at Vanderbilt.