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Radixin is a member of the ezrin/radixin/moesin (ERM) family of proteins, which
play a role in the formation of the membrane-associated cytoskeleton by linking
actin filaments and adhesion proteins. This cross-linking activity is regulated
by phosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP2) in the
downstream of the small G protein Rho. The X-ray crystal structures of the
radixin FERM domain, which is responsible for membrane binding, and its complex
with inositol-(1,4, 5)-trisphosphate (IP3) have been determined. The domain
consists of three subdomains featuring a ubiquitin-like fold, a four-helix
bundle and a phosphotyrosine-binding-like domain, respectively. These subdomains
are organized by intimate interdomain interactions to form characteristic
grooves and clefts. One such groove is negatively charged and so is thought to
interact with basic juxta-membrane regions of adhesion proteins. IP3 binds a
basic cleft that is distinct from those of pleckstrin homology domains and is
located on a positively charged flat molecular surface, suggesting an
electrostatic mechanism of plasma membrane targeting. Based on the structural
changes associated with IP3 binding, a possible unmasking mechanism of ERM
proteins by PIP2 is proposed.
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