Structural Basis for Discrimination of 3-Phosphoinositides by Pleckstrin Homology Domains

• Published in: Molecular cell 2000-08, Vol.6 (2), p.373-384
• Main Authors: Ferguson, Kathryn M., Kavran, Jennifer M., Sankaran, Vijay G., Fournier, Emmanuel, Isakoff, Steven J., Skolnik, Edward Y., Lemmon, Mark A.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Binding Sites; Blood Proteins - chemistry; Blood Proteins - metabolism; Crystallography, X-Ray; Fatty Acids - chemistry; Fatty Acids - metabolism; Hydrogen Bonding; Inositol Phosphates - metabolism; Lipoproteins; Models, Molecular; Molecular Sequence Data; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositols - metabolism; Protein Structure, Secondary; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; src Homology Domains; Substrate Specificity
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(00)00037-X

Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P 4, the head group of the major PI 3-K product PtdIns(3,4,5)P 3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P 3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P 3 and its 5′-dephosphorylation product, PtdIns(3,4)P 2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.