title: Structure of the binding site for inositol phosphates in a PH domain.
abstract: Phosphatidylinositol bisphosphate has been found to bind specifically to pleckstrin homology (PH) domains that are commonly present in signalling proteins but also found in cytoskeleton. We have studied the complexes of the beta-spectrin PH domain and soluble inositol phosphates using both circular dichroism and nuclear magnetic resonance spectroscopy, and X-ray crystallography. The specific binding site is located in the centre of a positively charged surface patch of the domain. The presence of 4,5-bisphosphate group on the inositol ring is critical for binding. In the crystal structure that has been determined at 2.0 A resolution, inositol-1,4,5-trisphosphate is bound with salt bridges and hydrogen bonds through these phosphate groups whereas the 1-phosphate group is mostly solvent-exposed and the inositol ring has virtually no interactions with the protein. We propose a model in which PH domains are involved in reversible anchoring of proteins to membranes via their specific binding to phosphoinositides. They could also participate in a response to a second messenger such as inositol trisphosphate, organizing cross-roads in cellular signalling.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hyvönen
authors.forename: M J
authors.initials: MJ
authors.lastname: Macias
authors.forename: M
authors.initials: M
authors.lastname: Nilges
authors.forename: H
authors.initials: H
authors.lastname: Oschkinat
authors.forename: M
authors.initials: M
authors.lastname: Saraste
authors.forename: M
authors.initials: M
authors.lastname: Wilmanns
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D007295:Inositol Phosphates / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010750:Phosphoproteins; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013049:Spectrin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D007295:Inositol Phosphates; D010750:Phosphoproteins; C039077:platelet protein P47; D013049:Spectrin