FUNCTION FROM STRUCTURE - THE CRYSTAL-STRUCTURE OF HUMAN PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN SUGGESTS A ROLE IN MEMBRANE SIGNAL-TRANSDUCTION

Background: Proteins belonging to the phosphatidylethanolamine-binding protein (PEBP) family are highly conserved throughout nature and have no significant sequence homology with other proteins of known structu re or function. A variety of biological roles have previously been des cribed for members of this family, including lipid binding, roles as o dorant effector molecules or opioids, interaction with the cell-signal ling machinery, regulation of flowering plant stem architecture, and a function as a precursor protein of a bioactive brain neuropeptide. To date, no experimentally derived structural information has been avail able for this protein family. In this study we have used X-ray crystal lography to determine the three-dimensional structure of human PEEP (h PEBP), in an attempt to clarify the biological role of this unique pro tein family. Results: The crystal structures of two forms of hPEBP hav e been determined: one in the native state (at 2.05 Angstrom resolutio n) and one in complex with cacodylate (at 1.75 Angstrom resolution). T he crystal structures reveal that hPEBP adopts a novel protein topolog y, dominated by the presence of a large central beta sheet, and is exp ected to represent the archaetypal fold for this family of proteins. T wo potential functional sites have been identified from the structure: a putative ligand-binding site and a coupled cleavage site. hPEBP for ms a dimer in the crystal with a distinctive dipole moment that may or ient the oligomer for membrane binding. Conclusions: The crystal struc ture of hPEBP suggests that the ligand-binding site could accommodate the phosphate head groups of membrane lipids, therefore allowing the p rotein to adhere to the inner leaf of bilipid membranes where it would be ideally positioned to relay signals from the membrane to the cytop lasm. The structure also suggests that ligand binding may lead to coor dinated release of the N-terminal region of the protein to form the hi ppocampal neurostimulatory peptide, which is known to be active in the development of the hippocampus. These studies are consistent with a p rimary biological role for hPEBP as a transducer of signals from the i nterior membrane surface.