# The Biological Significance of Calmodulin Binding to Lipids

## TL;DR

Calmodulin, a calcium-sensing protein, can bind to lipids, affecting protein localization and membrane integrity, with implications for cancer and cardiovascular diseases.

## Contribution

This paper is the first to review calmodulin's lipid-binding capabilities and their biological consequences.

## Key findings

- Calmodulin binds to lipid tails of prenylated proteins, pulling them out of membranes and altering their functions.
- Calmodulin binding to phosphatidylserine and phosphatidylethanolamine disrupts membrane integrity.
- Lipid binding can inhibit calmodulin's regulatory functions by displacing it from target proteins.

## Abstract

Calmodulin is a small, essential regulatory protein that senses and responds to cellular calcium ion levels. Its unprecedented ability to bind to and control over 100 proteins in the absence of calcium and more than 300 when activated by calcium has been well documented. Unexpectedly, calcium-activated calmodulin also binds to lipids, an event reviewed here for the first time. The binding occurs to the lipid tails of certain prenylated proteins that use the tail to localize to membranes. One effect of this binding is to pull the protein out of the membrane, in turn altering its functions, which is an event linked to multiple forms of cancer and certain cardiovascular diseases. Binding also occurs to individual lipids localized within membranes that can either tether calmodulin to them or disrupt membrane integrity. Lipid binding can also cause calmodulin to dislodge from binding proteins, thus inhibiting calmodulin’s regulatory functions. Calmodulin–lipid binding employs the identical binding region as calcium-mediated protein binding, potentially offering new options for therapeutic development. The multiple functions of calmodulin–lipid binding add further insight into the critical cellular and biomedical functions of this primary calcium sensor and effector.

In addition to binding to and regulating over 400 different proteins, calmodulin (CaM) also binds to lipids. Binding occurs to the prenylated tails of various small GTPases, to specific lipids in biological membranes and to free lipids in the cytoplasm. Here, CaM binding to Rac1, RalA, and KRAS4b is covered, emphasizing its importance in protein translocation from the cell membrane to the cytosol and its resultant impact on cell signaling. Binding phosphatidylserine and phosphatidylethanolamine in membranes not only leads to the tethering of CaM, but also to the disruption of lipid bilayers. Binding to sphingolipids also occurs, an event that acts as a competitive inhibitor of CaM function. The mechanism through which CaM binds to lipids is also examined. In total, the current state of affairs regarding calcium-dependent CaM–lipid binding is reviewed, including potential therapeutic uses, setting the stage for future work on this important biological event.