Annexins: Novel Ca*+-Dependent Regulators of Membrane Function

The annexins are a family of Ca*+-dependent membrane binding proteins that have been shown to regulate ion conductances, aggregate vesicles and the cytoskel-eton, inhibit phospholipase A, and inhibit blood coagulation. The annexins represent a unique mechanism of cellular regulation by modifying membrane functions in a Ca*+-dependent manner. A family of Ca2+-dependent phospholipid binding proteins has been identified by a number of laboratories with diverse experimen-tal goals. While these independent discoveries led initially to descriptively biased terminolo-gies, most groups working in the field have now accepted the general term annexins for these proteins due to the general property of binding and aggregating or “annexing ” membranes (3). Ca2+ acts to shift the annexins from a soluble to a membrane-associated state. The molecular structure of these proteins established their kinship (Fig. 1). Sequence re-peat domains of-70 amino acids are highly conserved and represent the protease-resistant, cr-helical-rich, Ca2+/phospholipid binding core. The NH,-terminal region of each annexin is variable in sequence and length and dictates unique cellular function. The NH,-terminal do-mains are sensitive to proteolysis, and many serve as excellent sites for protein kinase C and tyrosine kinase phosphorylation. Annexins I and II are major cellular tyosine kinase sub-strates for the epidermal growth factor receptor and the pp60 Rous sarcoma kinase, respec-tively. Phosphorylation alters the in vitro Ca2+-dependent phospholipid binding prop-erties and can be correlated with specific physiological states. The molecular topography of several annexins has been determined by X-ray crystallography. Huber and co-workers (4) demonstrated that the four sequence repeats correspond to four highly structured domains, each of which is composed of five homologous amphiphilic cx-helices. The four domains form a planar surface that binds to the anionic phospholipid surface of membranes