Structural basis of the membrane-targeting and unmasking mechanisms of theradixin FERM domain

Radixin is a member of the ezrin/radixin/moesin (ERM) family of proteins, w hich play a role in the formation of the membrane-associated cytoskeleton b y linking actin filaments and adhesion proteins. This cross-linking activit y is regulated by phosphoinositides such as phosphatidylinositol 4,5-bispho sphate (PIP2) in the downstream of the small G protein Rho, The X-ray cryst al structures of the radixin FERM domain, which is responsible for membrane binding, and its complex with inositol-(1,4,5)-trisphosphate (IP3) have be en determined. The domain consists of three subdomains featuring a ubiquiti n-like fold, a four-helix bundle and a phosphotyrosine-binding-like domain, respectively. These subdomains are organized by intimate interdomain inter actions to form characteristic grooves and clefts. One such groove is negat ively charged and so is thought to interact with basic juxta-membrane regio ns of adhesion proteins. IP3 binds a basic cleft that is distinct from thos e of pleckstrin homology domains and is located on a positively charged fla t molecular surface, suggesting an electrostatic mechanism of plasma membra ne targeting. Based on the structural changes associated with IP3 binding, a possible unmasking mechanism of ERM proteins by PIP2 is proposed.