Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p

Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 Angstrom structure of the Vps27p FYVE domain reveals two antiparallel beta sheets and an alpha helix stabilized by two Zn2+-binding clusters. The core secondary structures are similar to a rabphilin-3A Zn2+-binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to phosphatidylinositol 3-phosphate.