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Science. 2017 Dec 15;358(6369):1448-1453. doi: 10.1126/science.aao4165. Epub 2017 Nov 16.

Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation.

Author information

1
Grenoble Institut des Neurosciences (GIN), Université Grenoble Alpes, F-38000 Grenoble, France.
2
Inserm, U1216, F-38000 Grenoble, France.
3
Institut de Génétique Humaine (IGH), Université Montpellier, CNRS UMR9002, 34000 Montpellier, France.
4
Centre de Recherche en Biochimie Macromoléculaire (CRBM), Université Montpellier, CNRS UMR5237, 34000 Montpellier, France.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Institut de Biosciences et Biotechnologies de Grenoble (BIG)-Laboratoire Biologie à Grande Échelle, Université Grenoble Alpes, CEA, INSERM, F-38000 Grenoble, France.
7
Team Regulation and Pharmacology of the Cytoskeleton, Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, 38000 Grenoble, France.
8
BIG-Physiopathologie du Cytosquelette, CEA, F-38000 Grenoble, France.
9
Grenoble Institut des Neurosciences (GIN), Université Grenoble Alpes, F-38000 Grenoble, France. moutinm@univ-grenoble-alpes.fr annie.andrieux@univ-grenoble-alpes.fr krzysztof.rogowski@igh.cnrs.fr.

Abstract

Reversible detyrosination of α-tubulin is crucial to microtubule dynamics and functions, and defects have been implicated in cancer, brain disorganization, and cardiomyopathies. The identity of the tubulin tyrosine carboxypeptidase (TCP) responsible for detyrosination has remained unclear. We used chemical proteomics with a potent irreversible inhibitor to show that the major brain TCP is a complex of vasohibin-1 (VASH1) with the small vasohibin binding protein (SVBP). VASH1 and its homolog VASH2, when complexed with SVBP, exhibited robust and specific Tyr/Phe carboxypeptidase activity on microtubules. Knockdown of vasohibins or SVBP and/or inhibitor addition in cultured neurons reduced detyrosinated α-tubulin levels and caused severe differentiation defects. Furthermore, knockdown of vasohibins disrupted neuronal migration in developing mouse neocortex. Thus, vasohibin/SVBP complexes represent long-sought TCP enzymes.

PMID:
29146868
DOI:
10.1126/science.aao4165
[Indexed for MEDLINE]

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