Structural Basis of 3-Phosphoinositide Recognition by Pleckstrin Homology Domains

• Published in: Molecular cell 2000-08, Vol.6 (2), p.385-394
• Main Authors: Lietzke, Susan E., Bose, Sahana, Cronin, Thomas, Klarlund, Jes, Chawla, Anil, Czech, Michael P., Lambright, David G.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Binding Sites; Conserved Sequence; Crystallography, X-Ray; Inositol Phosphates - metabolism; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositols - metabolism; Protein Conformation; Protein Structure, Secondary; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sequence Alignment; Sequence Homology, Amino Acid; src Homology Domains
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(00)00038-1

Lipid second messengers generated by phosphoinositide (PI) 3-kinases regulate diverse cellular functions through interaction with pleckstrin homology (PH) domains in modular signaling proteins. The PH domain of Grp1, a PI 3-kinase-activated exchange factor for Arf GTPases, selectively binds phosphatidylinositol 3,4,5-trisphosphate with high affinity. We have determined the structure of the Grp1 PH domain in the unliganded form and bound to inositol 1,3,4,5-tetraphosphate. A novel mode of phosphoinositide recognition involving a 20-residue insertion within the β6/β7 loop explains the unusually high specificity of the Grp1 PH domain and the promiscuous 3-phosphoinositide binding typical of several PH domains including that of protein kinase B. When compared to other PH domains, general determinants of 3-phosphoinositide recognition and specificity can be deduced.