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Bioinformatics Advance Access published online on July 14, 2006
Bioinformatics, doi:10.1093/bioinformatics/btl381
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© The Author (2006). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received February 9, 2006
Revised June 6, 2006
Accepted July 6, 2006

Discovery note

Scoring of predicted GRK2 phosphorylation sites in Nedd4-2

Jonathan W. Arthur 1 *, Angeles Sanchez-Perez 2, and David I. Cook 3

1 Department of Medicine, University of Sydney, Sydney, Australia, 2006; Sydney University Biological Informatics and Technology Centre, University of Sydney, Sydney Australia, 2006
2 Department of Pathology, University of Sydney, Sydney Australia, 2006
3 Department of Physiology, University of Sydney, Sydney, Australia, 2006

* To whom correspondence should be addressed.
Jonathan W. Arthur, E-mail: jarthur{at}med.usyd.edu.au


  Abstract

Motivation: Epithelial Na+ channels (ENaC) mediate the transport of sodium (Na) across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4-2. These ligases bind to proline-rich motifs (PY motifs) present in the C-termini of ENaC subunits. Loss of this inhibition leads to hypertension. We have previously reported (Dinudom et al., 2004) that ENaC channels are maintained in the active state by the G protein coupled receptor kinase, GRK2. The enzyme has been implicated in the development of essential hypertension (Feldman, 2002). Additional findings in our lab pointed towards a possible role for GRK2 in the phosphorylation and inactivation of Nedd4-2.

Results: We have predicted GRK2 phosphorylation sites on Nedd4-2 by combining sequence analysis, homology modeling, and surface accessibility calculations. Twenty four potential phosphorylation sites were predicted by sequence analysis. Of these, sixteen could be modeled using homology modeling and six of these were found to have sufficient surface exposure to be accessible to the GRK2 enzyme responsible for the phosphorylation of Nedd4-2. The method provides an ordered list of the most likely GRK2 phosphorylation sites on Nedd4-2 providing invaluable guidance to future experimental studies aimed at mutating certain Nedd4-2 residues in order to prevent phosphorylation by GRK2. The method developed could be applied in a wide variety of biological applications involving the binding of one molecule to a protein. The relative effectiveness of the technique is determined mainly by the quality of the homology model built for the protein of interest.

Associate Editor: Anna Tramontano
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