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Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event
Adele M. Snowman*,
Adam C. Resnick*,,
Troels Z. Kristiansen¶,
J. Kent Werner, Jr.*,
Krishna R. Juluri*,
Glenn D. Prestwich||,
Keykavous Parang, and
Solomon H. Snyder*,**,,
*The Solomon H. Snyder Department of Neuroscience, Departments of **Pharmacology and Molecular Sciences, Psychiatry and Behavioral Sciences, and ¶McKusick–Nathans Institute of Genetic Medicine and Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881; and ||Department of Medicinal Chemistry, University of Utah, 419 Wakara Way,Suite 205, Salt Lake City, UT 84108
Contributed by Solomon H. Snyder, August 3, 2007
Received for publication July 16, 2007.
In a previous study, we showed that the inositol pyrophosphatediphosphoinositol pentakisphosphate (IP7) physiologically phosphorylatesmammalian and yeast proteins. We now report that this phosphatetransfer reflects pyrophosphorylation. Thus, proteins must beprephosphorylated by ATP to prime them for IP7 phosphorylation.IP7 phosphorylates synthetic phosphopeptides but not if theirphosphates have been masked by methylation or pyrophosphorylation.Moreover, IP7 phosphorylated peptides are more acid-labile andmore resistant to phosphatases than ATP phosphorylated peptides,indicating a different type of phosphate bond. Pyrophosphorylationmay represent a novel mode of signaling to proteins.
Key Words: inositol polyphosphate protein phosphorylation
Author contributions: R.B., A.S., Y.A., A.C.R., K.P., and S.H.S.designed research; R.B., Y.A., A.M.S., A.C.R., J.K.W., and K.R.J.performed research; T.Z.K., H.M., A.P., Y.X., and G.D.P. contributednew reagents/analytic tools; R.B., A.S., and S.H.S. analyzeddata; and R.B., G.D.P., K.P., and S.H.S. wrote the paper.
Present address: Division of Neurosurgery, Children's Hospitalof Philadelphia, Department of Neurosurgery, University of PennsylvaniaSchool of Medicine, Philadelphia, PA 19104.