Multivalent endosome targeting by homodimeric EEA1

Early endosome autoantigen localization to early endosomes is mediated by a C-terminal region, which includes a calmodulin binding motif, a Rab5 inter action site, and a FYVE domain that selectively binds phosphatidyl inositol 3-phosphate. The crystal structure of the C-terminal region bound to inosi tol 1,3-bisphosphate reveals an organized, quaternary assembly consisting o f a parallel coiled coil and a dyad-symmetric FYVE domain homodimer. Struct ural and biochemical observations support a multivalent mechanism for endos omal localization in which domain organization, dimerization, and quaternar y structure amplify the weak affinity and modest specificity of head group interactions with conserved residues. A unique mode of membrane engagement deduced from the quaternary structure of the C-terminal region provides ins ight into the structural basis of endosome tethering.