Calmodulin: The Essential Biological Regulator Self-Regulates Its Activity, Structure and Function

Calmodulin is an evolutionarily conserved critical controller protein found in animals, plants, fungi, and microbes. As the primary calcium sensor and effector in eukaryotes, calmodulin translates calcium signals into vital biological responses by binding to and regulating calmodulin-binding proteins. While it was previously shown to control several hundred proteins, evidence now indicates it binds to over 100 in its calcium-free state and more than 500 when activated by calcium ions. While calmodulin function is modulated by calcium levels, the final cytosolic levels of calcium are often under calmodulin's control. Human calmodulin is encoded by three unique genes (CALM1-3), each of which produces an identical functional protein. The CALM genes are among the most mutation-intolerant sequences in the human genome. They are under the control of two calmodulin-binding transcription activators (CAMTAs) that are also ancient, highly conserved, and, as their name implies, under the control of calmodulin. Thus, calmodulin controls the transcription of the genes that encode it. Finally, two primary post-translational events that affect the function and stability of calmodulin are also regulated by it: methylation, which stabilizes the functional protein, and phosphorylation, which regulates its activity as needed. This review covers those topics to reveal that calmodulin controls its own expression, structure, and function, reflecting its unique position as an essential major regulator of cell function.