Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation
Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation
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DOI：
10.1126/science.aao4165
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发表时间：
2017-12-15
期刊：
影响因子：
56.9
通讯作者：
Moutin, Marie-Jo
中科院分区：
文献类型：
--
作者：
Aillaud, Chrystelle;Bosc, Christophe;Moutin, Marie-Jo
微管蛋白的可逆去酪氨酸对微管动力学和功能至关重要，其缺陷与癌症、脑紊乱和心肌病有关。负责去酪氨酸的微管蛋白酪氨酸羧肽酶（TCP）的身份仍然不清楚。我们使用化学蛋白质组学和一种有效的不可逆抑制剂来证明主要的脑TCP是vasohibin-1 （VASH1）与小vasohibin结合蛋白（SVBP）的复合体。当VASH1及其同源物VASH2与SVBP络合时，在微管上表现出强大的特异性Tyr/Phe羧肽酶活性。在培养的神经元中敲低血管球蛋白或SVBP和/或添加抑制剂可降低去酪氨酸α -微管蛋白水平，并引起严重的分化缺陷。此外，血管收缩蛋白的敲低会破坏发育中的小鼠新皮层中的神经元迁移。因此，vasohibin/SVBP复合物代表了长期寻找的TCP酶。
Reversible detyrosination of alpha-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 alpha-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.