期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 18, 页码 11892-11899出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806205200
关键词
-
资金
- National Institutes of Health [GM074887]
We have investigated the possible biochemical basis for enhancements in NO production in endothelial cells that have been correlated with agonist- or shear stress-evoked phosphorylation at Ser-1179. We have found that a phosphomimetic substitution at Ser-1179 doubles maximal synthase activity, partially disinhibits cytochrome c reductase activity, and lowers the EC50(Ca2+) values for calmodulin binding and enzyme activation from the control values of 182 +/- 2 and 422 +/- 22 nMto 116 +/- 2 and 300 +/- 10 nM. These are similar to the effects of a phosphomimetic substitution at Ser-617 (Tran, Q. K., Leonard, J., Black, D. J., and Persechini, A. (2008) Biochemistry 47, 7557-7566). Although combining substitutions at Ser-617 and Ser-1179 has no additional effect on maximal synthase activity, cooperativity between the two substitutions completely disinhibits reductase activity and further reduces the EC50(Ca2+) values for calmodulin binding and enzyme activation to 77 +/- 2 and 130 +/- 5 nM. We have confirmed that specific Akt-catalyzed phosphorylation of Ser-617 and Ser- 1179 and phosphomimetic substitutions at these positions have similar functional effects. Changes in the biochemical properties of eNOS produced by combined phosphorylation at Ser- 617 and Ser- 1179 are predicted to substantially increase synthase activity in cells at a typical basal free Ca2+ concentration of 50-100 nM.
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