Sticking to Membranes: Structure, Function, and Cellular Roles of the Annexin Family of Ca²⁺- and Membrane-Binding Proteins

Intracellular calcium (Ca²⁺) signaling is shaped by the coordinated action of pumps, channels, transporters, and Ca²⁺-binding proteins including the cytosolic annexins, which decode changes in cellular Ca²⁺ levels and are crucial components of this intricate system. Here, we dissect overarching themes in annexin biology, detailing their structure, functional capabilities, and roles within the cellular context. We describe their bimodular structure consisting of the core domain with the Ca²⁺- and membrane-binding sites that classify the proteins and the amino-terminal domain containing sites for proteolytic cleavage, phosphorylation, and protein interaction including complex formation with S100 family Ca²⁺-binding proteins. We examine their Ca²⁺ sensing and lipid/membrane binding properties and discuss experimental evidence toward their functions in building Ca²⁺-controlled platforms for dynamic assembly of functional machineries at specific membrane domains within the complex regulatory networks of cellular function.