Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains

Pleckstrin homology (PH) domains are protein modules of around 120 amino ac ids found in many proteins involved in cellular signaling. Certain PH domai ns drive signal-dependent membrane recruitment of their host proteins by bi nding strongly and specifically to lipid second messengers produced by agon ist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crys tal structures of two different PH domains bound to Ins(1,3,4,5)P-4, the he ad group of the major PI 3-K product PtdIns(3,4,5)P-3. One of these PH doma ins (from Grp1) is PtdIns(3,4,5)P-3 specific, while the other (from DAPP1/P HISH) binds strongly to both Ptdlns(3,4,5)P-3 and its 5'-dephosphorylation product, Ptdlns(3,4)P-2. Comparison of the two structures provides an expla nation for the distinct phosphoinositide specificities of the two PH domain s and allows us to predict the 3-phosphoinositide selectivity of uncharacte rized PH domains.