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First published online August 24, 2006
doi: 10.1242/10.1242/jcs.03149

Journal of Cell Science 119, 3634-3642 (2006)
Published by The Company of Biologists 2006
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Research Article

Ubiquitin protein ligase Nedd4 binds to connexin43 by a phosphorylation-modulated process

Kerstin Leykauf1,*, Mojibrahman Salek1, Jörg Bomke2, Matthias Frech2, Wolf-Dieter Lehmann1, Matthias Dürst3 and Angel Alonso1,*

1 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld-242, 69120 Heidelberg, Germany
2 Merck KGaA, Frankfurterstr. 250, 64293 Darmstadt, Germany
3 Klinik für Frauenheilkunde und Geburtshilfe, University of Jena, Bachstr. 18, 07740 Jena, Germany

* Authors for correspondence (e-mail: k.leykauf{at}dkfz.de; a.alonso{at}dkfz.de)

Accepted 20 June 2006

Connexin43 is degraded by the proteasomal as well as the lysosomal pathway with ubiquitin playing a role in both degradation pathways. So far, no ubiquitin protein ligase has been identified for any of the connexins. By using pull-down assays, here we show binding of a ubiquitin protein ligase, Nedd4, to the C-terminus of connexin43. This observation was confirmed in vivo by coimmunoprecipitation and immunofluorescence, showing colocalization of Nedd4 and connexin43. Binding of Nedd4 to its interaction partners is generally carried out by its WW domains. Our results indicate that the interaction with connexin43 occurs through all three WW domains of Nedd4. Furthermore, whereas WW1 and WW2 domains mainly interact with the unphosphorylated form of connexin43, WW3 binds phosphorylated and unphosphorylated forms equally. In addition, using the surface plasmon resonance approach we show that only the WW2 domain binds to the PY motif located at the C-terminus of connexin43. Suppression of Nedd4 expression with siRNA resulted in an accumulation of gap junction plaques at the plasma membrane, suggesting an involvement of the ubiquitin protein ligase Nedd4 in gap junction internalization.

Key words: Connexin, Gap junction, PY motif, Ubiquitylation, WW domains


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© The Company of Biologists Ltd 2006