TY - JOUR
T1 - Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains
AU - Ferguson, Kathryn M.
AU - Kavran, Jennifer M.
AU - Sankaran, Vijay G.
AU - Fournier, Emmanuel
AU - Isakoff, Steven J.
AU - Skolnik, Edward Y.
AU - Lemmon, Mark A.
N1 - Funding Information:
We are sincerely grateful to Professor Greg Van Duyne for his generosity with crystallographic advice and equipment, and many valuable discussions and comments on the manuscript. We also thank Malcolm Capel and Hal Lewis of the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory for help in data collection. The NSLS is supported by the US Department of Energy, Division of Materials Sciences and Division of Chemical Sciences, under contract number DE-AC02-98CH10886. X25 is supported in part by the National Institutes of Health (NIH), the National Center for Research Resources, and the US Department of Energy, Office of Biological and Environmental Research. These projects were supported by the NIH (NIGMS grant GM56846 to M. A. L.; NIDDK grant DK49207 to E. Y. S.), the US Army Breast Cancer Research Program (DAMD17-98-1-8228 to K. M. F.), and a Damon Runyon Scholar Award from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (to M. A. L.).
PY - 2000
Y1 - 2000
N2 - 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)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns (3,4)P2. 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.
AB - 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)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns (3,4)P2. 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.
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U2 - 10.1016/S1097-2765(00)00037-X
DO - 10.1016/S1097-2765(00)00037-X
M3 - Article
C2 - 10983984
AN - SCOPUS:0033635275
SN - 1097-2765
VL - 6
SP - 373
EP - 384
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -