title: Multivalent endosome targeting by homodimeric EEA1.
abstract: Early endosome autoantigen localization to early endosomes is mediated by a C-terminal region, which includes a calmodulin binding motif, a Rab5 interaction site, and a FYVE domain that selectively binds phosphatidyl inositol 3-phosphate. The crystal structure of the C-terminal region bound to inositol 1,3-bisphosphate reveals an organized, quaternary assembly consisting of a parallel coiled coil and a dyad-symmetric FYVE domain homodimer. Structural and biochemical observations support a multivalent mechanism for endosomal localization in which domain organization, dimerization, and quaternary 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 insight into the structural basis of endosome tethering.
authors.affiliation: Program in Molecular Medicine and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Dumas
authors.forename: E
authors.initials: E
authors.lastname: Merithew
authors.forename: E
authors.initials: E
authors.lastname: Sudharshan
authors.forename: D
authors.initials: D
authors.lastname: Rajamani
authors.forename: S
authors.initials: S
authors.lastname: Hayes
authors.forename: D
authors.initials: D
authors.lastname: Lawe
authors.forename: S
authors.initials: S
authors.lastname: Corvera
authors.forename: D G
authors.initials: DG
authors.lastname: Lambright
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D011992:Endosomes / Q000378:metabolism*; D007295:Inositol Phosphates / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D033921:Vesicular Transport Proteins; D016335:Zinc Fingers; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D001324:Autoantigens; D007295:Inositol Phosphates; D008565:Membrane Proteins; D010743:Phospholipids; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C051853:inositol 1,3-bisphosphate; D020696:rab5 GTP-Binding Proteins