The Rab 11 family of interacting proteins (Rab11-FIP) is a recently identified protein family composed of, to date, six members that interact with Rab11. They all share a highly homologous Rab11-binding domain (RBD) at their C-termini. However, apart from the RBD, they vary in their domain organization. Rab11-FIP3 and Rab11-FIP4 possess an ezrin-radixin-moesin (ERM) domain in their C-terminal half and EF hands in their N-terminal region. They have been termed class II Rab11-FIPs. The class I Rab11-FIPs, Rab coupling protein (RCP), Rip11 and Rab11-FIP2, each have a C2 phospholipid-binding domain near their N-termini. Although they are still membrane associated, truncation mutants of the class I Rab11-FIPs that lack their C2 domains display an altered subcellular distribution in vivo, indicating that this domain plays an important role in specifying their correct intracellular localization. To determine the phospholipids to which they bind, a protein phospholipid overlay assay was performed. Our results indicate that the class-I Rab11-FIPs bind preferentially to phosphatidylinositol-(3,4,5)-trisphosphate [PtdIns(3,4,5)P3] and the second messenger phosphatidic acid. Stimulation of PtdIns(3,4,5)P3 or phosphatidic acid synthesis results in the translocation of the Rab11-FIPs from a perinuclear location to the periphery of the cell. By contrast, the transferrin receptor does not translocate to the plasma membrane under these conditions. This translocation is dependent on the presence of the C2 domain, because class I Rab11-FIP green-fluorescent-protein fusions that lack the C2 domain cannot translocate to the plasma membrane. We propose that the C2 domains of the class I Rab11-FIPs function to target these proteins to 'docking sites' in the plasma membrane that are enriched in PtdIns(3,4,5)P3 and phosphatidic acid.
Lindsay, A. J., & McCaffrey, M. W. (2004). The C2 domains of the class I Rab11 family of interacting proteins target recycling vesicles to the plasma membrane. Journal of Cell Science, 117(19), 4365–4375. https://doi.org/10.1242/jcs.01280