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J. Biol. Chem., Vol. 283, Issue 7, 3915-3922, February 15, 2008

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Polyglutamylation Is a Post-translational Modification with a Broad Range of Substrates^*

Juliette van Dijk, Julie Miro, Jean-Marc Strub, Benjamin Lacroix, Alain van Dorsselaer, Bernard Edde^¶, and Carsten Janke¹

From the Centre de Recherche de Biochimie Macromoléculaire, Universités Montpellier 2 and 1, CNRS, 34293 Montpellier, France, the Laboratoire de Spectrométrie de Masse BioOrganique, CNRS, 67087 Strasbourg, France, and the ^¶Université Paris 6, 75252 Paris, France

Polyglutamylation is a post-translational modification that generates lateral acidic side chains on proteins by sequential addition of glutamate amino acids. This modification was first discovered on tubulins, and it is important for several microtubule functions. Besides tubulins, only the nucleosome assembly proteins NAP1 and NAP2 have been shown to be polyglutamylated. Here, using a proteomic approach, we identify a large number of putative substrates for polyglutamylation in HeLa cells. By analyzing a selection of these putative substrates, we show that several of them can serve as in vitro substrates for two of the recently discovered polyglutamylases, TTLL4 and TTLL5. We further show that TTLL4 is the main polyglutamylase enzyme present in HeLa cells and that new substrates of polyglutamylation are indeed modified by TTLL4 in a cellular context. No clear consensus polyglutamylation site could be defined from the primary sequence of the here-identified new substrates of polyglutamylation. However, we demonstrate that glutamate-rich stretches are important for a protein to become polyglutamylated. Most of the newly identified substrates of polyglutamylation are nucleocytoplasmic shuttling proteins, including many chromatin-binding proteins. Our work reveals that polyglutamylation is a much more widespread post-translational modification than initially thought and thus that it might be a regulator of many cellular processes.

Received for publication, July 16, 2007 , and in revised form, November 27, 2007.

^* This work was supported in part by the CNRS, the Universities Montpellier 1 and 2, Association de la Recherche contre le Cancer Awards CR504/7817 and 3140 (to C. J.), French National Research Agency Award JC05_42022 (to C. J.), and the La Ligue contre le Cancer (to C. J. and B. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: CRBM, CNRS, 1919 Route de Mende, 34293 Montpellier, France. Tel.: 33-4-67613335; Fax: 33-4-67521559; E-mail: carsten.janke{at}crbm.cnrs.fr.

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