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PNAS 104 (39): 15305-15310

Copyright © 2007 by the National Academy of Sciences.


Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event

Rashna Bhandari*, Adolfo Saiardi{dagger}, Yousef Ahmadibeni{ddagger}, Adele M. Snowman*, Adam C. Resnick*,§, Troels Z. Kristiansen, Henrik Molina, Akhilesh Pandey, J. Kent Werner, Jr.*, Krishna R. Juluri*, Yong Xu||, Glenn D. Prestwich||, Keykavous Parang{ddagger}, and Solomon H. Snyder*,**,{dagger}{dagger},{ddagger}{ddagger}

*The Solomon H. Snyder Department of Neuroscience, Departments of **Pharmacology and Molecular Sciences, {dagger}{dagger}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; {dagger}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; {ddagger}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.

Abstract: In a previous study, we showed that the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7) physiologically phosphorylates mammalian and yeast proteins. We now report that this phosphate transfer reflects pyrophosphorylation. Thus, proteins must be prephosphorylated by ATP to prime them for IP7 phosphorylation. IP7 phosphorylates synthetic phosphopeptides but not if their phosphates have been masked by methylation or pyrophosphorylation. Moreover, IP7 phosphorylated peptides are more acid-labile and more resistant to phosphatases than ATP phosphorylated peptides, indicating a different type of phosphate bond. Pyrophosphorylation may 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. contributed new reagents/analytic tools; R.B., A.S., and S.H.S. analyzed data; and R.B., G.D.P., K.P., and S.H.S. wrote the paper.

§Present address: Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.

The authors declare no conflict of interest.

This article contains supporting information online at

{ddagger}{ddagger}To whom correspondence should be addressed at: 725 North Wolfe Street, WBSB 813, Baltimore, MD 21205. E-mail: ssnyder{at}

© 2007 by The National Academy of Sciences of the USA

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