title: A family of protein-deglutamylating enzymes associated with neurodegeneration.
abstract: 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.
authors.affiliation: CRBM, Université Montpellier 2 and 1, CNRS UMR 5237, Montpellier 34293, France. krzysztof.rogowski@crbm.cnrs.fr
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rogowski
authors.forename: Juliette
authors.initials: J
authors.lastname: van Dijk
authors.forename: Maria M
authors.initials: MM
authors.lastname: Magiera
authors.forename: Christophe
authors.initials: C
authors.lastname: Bosc
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Deloulme
authors.forename: Anouk
authors.initials: A
authors.lastname: Bosson
authors.forename: Leticia
authors.initials: L
authors.lastname: Peris
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gold
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lacroix
authors.forename: Montserrat
authors.initials: M
authors.lastname: Bosch Grau
authors.forename: Nicole
authors.initials: N
authors.lastname: Bec
authors.forename: Christian
authors.initials: C
authors.lastname: Larroque
authors.forename: Solange
authors.initials: S
authors.lastname: Desagher
authors.forename: Max
authors.initials: M
authors.lastname: Holzer
authors.forename: Annie
authors.initials: A
authors.lastname: Andrieux
authors.forename: Marie-Jo
authors.initials: MJ
authors.lastname: Moutin
authors.forename: Carsten
authors.initials: C
authors.lastname: Janke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D002531:Cerebellum / Q000473:pathology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism*; D009830:Olfactory Bulb / Q000473:pathology; D011099:Polyglutamic Acid / Q000378:metabolism*; D016415:Sequence Alignment; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D014404:Tubulin; D011099:Polyglutamic Acid; D002268:Carboxypeptidases; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C420042:Agtpbp1 protein, mouse; D019204:GTP-Binding Proteins