Enhancement of phosphoinositide 3-kinase (PI 3-kinase) activity by membrane curvature and inositol-phospholipid-binding peptides.
The phosphorylation of phosphatidylinositol (PtdIns) on the 3' position of the inositol ring by phosphoinositide 3-kinase (PI 3-kinase) is shown to depend strongly on the curvature of liposomes containing a mixture of phosphatidylcholine (PtdCho) and PtdIns. Vesicles with an average diameter of 50 nm are phosphorylated 100 times faster than chemically identical vesicles with an average diameter greater than 300 nm. The low reactivity of large vesicles is not due to the difference in vesicle number for large and small vesicles at constant total lipid, nor to occlusion of lipid surfaces in multilammelar structures, and can be reversed by addition of low (< 1:100) molar ratios of either the PtdIns transfer protein sec14p or a ten-residue peptide derived from the inositol-phospholipid-binding site of gelsolin. Similar measurements using PI 4-kinase showed a weak dependence on vesicle size. The strong dependence of PI 3-kinase function on membrane curvature suggests possible localization of PI 3-kinase activity at sites where clustering of receptors, for example, may locally deform the membrane, and suggests that once PI 3-kinase is localized and activated at surface sites, the reaction may become self-accelerating.
Hübner
S
S
Experimental Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
Couvillon
A D
AD
Käs
J A
JA
Bankaitis
V A
VA
Vegners
R
R
Carpenter
C L
CL
Janmey
P A
PA
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004339:Drug Compounding; D004789:Enzyme Activation; D005456:Fluorescent Dyes / Q000378:metabolism; D018260:Gelsolin / Q000737:chemistry; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008565:Membrane Proteins; D010316:Particle Size; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins; D051381:Rats; D013499:Surface Properties
D002352:Carrier Proteins; D005456:Fluorescent Dyes; D018260:Gelsolin; D008051:Lipid Bilayers; D008081:Liposomes; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D010716:Phosphatidylinositols; D049294:Phospholipid Transfer Proteins; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D019870:1-Phosphatidylinositol 4-Kinase