Structure of the pleckstrin homology domain from β-spectrin

Abstract

THE ‘pleckstrin homology’ or PH domain is a 100-residue protein module. It is present in many kinases, different isoforms of phospholipase C, GTPase-activating proteins and nucleotide-exchange factors1–4. Its function is not known, but many proteins that contain a PH domain interact with GTP-binding proteins5. The PH domain in β-adrenergic receptor kinase may be involved in binding to the βγ subunits of a trimeric G-protein3, 4, 6, 7. We report here the three-dimensional structure of the PH domain of the cytoskeletal protein spectrin using homonuclear nuclear magnetic resonance. The core of the molecule is an antiparallel β-sheet consisting of seven strands. The C terminus is folded into a long α-helix, and another helix is present in one of the surface loops. The molecule is electrostatically polarized and contains a pocket which may be involved in the binding of a ligand. There is a distant relationship to the peptidyl-prolyl-cis-trans-isomerase FKBP in which this pocket is involved in the binding of the macrocyclic compound FK506(refs 8–11).