Ca2+ and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] are key agents in membrane-associated signalling events. Their temporal and spatial regulation is crucial for activation or recruitment of proteins in the plasma membrane. In fact, the interaction of several signalling proteins with PI(4,5)P2 has been shown to be tightly regulated and dependent on the presence of Ca2+, with co-operative binding in some cases. In these proteins, PI(4,5)P2 and Ca2+ binding typically occurs at different binding sites. In addition, several PI(4,5)P2-binding proteins are known targets of calmodulin (CaM), which, depending on the presence of calcium, can compete with PI(4,5)P2 for protein interaction, translating Ca2+ transient microdomains into variations of PI(4,5)P2 lateral organization in time and space. The present review highlights different examples of calcium-dependent PI(4,5)P2-binding proteins and discusses the possible impact of this dual regulation on fine-tuning of protein activity by triggering target membrane binding in the presence of subtle changes in the levels of calcium or PI(4,5)P2.

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