Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.
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.
Ferguson
K M
KM
Department of Biochemistry and Biophysics and The Johnson Foundation, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Kavran
J M
JM
Sankaran
V G
VG
Fournier
E
E
Isakoff
S J
SJ
Skolnik
E Y
EY
Lemmon
M A
MA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007295:Inositol Phosphates / Q000378:metabolism*; D008074:Lipoproteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013379:Substrate Specificity; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C486555:DAPP1 protein, human; D005227:Fatty Acids; D007295:Inositol Phosphates; D008074:Lipoproteins; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases