Annexins are a family of cakcium- and phospholipid-binding proteins implicated in mediating membrane-related processes such as secretion, signal transduction, and ion channel activity. Structural evidence has been obtained for a Ca~'-bridging mechanism, proposed for Ca2'-binding interfacial membrane proteins such as annexins, protein kinase C, and certain coagulation proteins. Crystal structures of Ca~'-annexin V complexes with phospholipid polar heads provide molecular details of Ca~'-bridges as key features in the membrane attachment exhibited by these proteins. Distinct binding sites for phospholipid head groups are observed, including a novel, double-Ca~' recognition site for phosphoserine that may serve as a phosphatidylserine receptor site in vivo. We have solved the crystal structure of rat annexin V to 1.9 angstrom resolution by multiple isomorphous replacement. Unlike previously solved annexin V structures, all four domains bound calcium in this structure. Calcium binding in the third domain induced a large relocation of the calcium-binding loop regions, exposing the single tryptophan residue to the solvent. These alterations in annexin V suggest a role for domain 3 in calcium-triggered interaction with phospholipid membranes. Mass spectrometry experiments are being used to obtain profiles of the phospholipids associated with annexin V.
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