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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / genetics
  • Angiogenic Proteins / metabolism*
  • Animals
  • Carboxypeptidases / genetics
  • Carboxypeptidases / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Movement
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Neocortex / cytology
  • Neocortex / embryology
  • Neurogenesis*
  • Neurons / cytology*
  • Neurons / enzymology
  • Proteomics
  • Tubulin / metabolism
  • Tyrosine / metabolism*

Substances

  • Angiogenic Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • SVBP protein, human
  • Tubulin
  • VASH1 protein, human
  • VASH2 protein, human
  • Tyrosine
  • Carboxypeptidases
  • tyrosyltubulin carboxypeptidase