A family of protein-deglutamylating enzymes associated with neurodegeneration.

Krzysztof Rogowski (1) , Juliette van Dijk (1) , Maria M. Magiera (1) , Christophe Bosc (2) , Jean-Christophe Deloulme (2) , Anouk Bosson (2) , Leticia Peris (2) , Nicholas D. Gold (1) , Benjamin Lacroix (1) , Montserrat Bosch Grau (1) , Nicole Bec (3) , Christian Larroque (3) , Solange Desagher (4) , Max Holzer (5) , Annie Andrieux (2) , Marie-Jo Moutin (2) , Carsten Janke (1)

1 CRBM - Centre de recherche en Biologie Cellulaire
2 GIN - Grenoble Institut des Neurosciences
3 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
4 IGMM - Institut de Génétique Moléculaire de Montpellier
5 Paul-Flechsig-Institute of Brain Research

Polyglutamylation is a posttranslational modification that generates glutamate side chains on tubulins and other proteins. Although this modification has been shown to be reversible, little is known about the enzymes catalyzing deglutamylation. Here we describe the enzymatic mechanism of protein deglutamylation by members of the cytosolic carboxypeptidase (CCP) family. Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains and a fourth (CCP5) specifically removes the branching point glutamates. In addition, CCP1, CCP4, and CCP6 also remove gene-encoded glutamates from the carboxyl termini of proteins. Accordingly, we show that these enzymes convert detyrosinated tubulin into Δ2-tubulin and also modify other substrates, including myosin light chain kinase 1. We further analyze Purkinje cell degeneration (pcd) mice that lack functional CCP1 and show that microtubule hyperglutamylation is directly linked to neurodegeneration. Taken together, our results reveal that controlling the length of the polyglutamate side chains on tubulin is critical for neuronal survival.

Mots clés: Tubulin; microtubules; polyglutamylation; deglutamylation; cytosolic carboxy peptidase; CCP; pcd mouse; neurodegeneration; Nna1; polyglutamylase; TTLL

Domaines: Biochimie, Biologie Moléculaire

Krzysztof Rogowski, Juliette van Dijk, Maria M. Magiera, Christophe Bosc, Jean-Christophe Deloulme, et al.. A family of protein-deglutamylating enzymes associated with neurodegeneration.. Cell, 2010, 143 (4), pp.564-78. ⟨10.1016/j.cell.2010.10.014⟩. ⟨hal-00538184⟩