Tubulin carboxypeptidase identity revealed Enzymes of the α-tubulin detyrosination/tyrosination cycle create landmarks on microtubules that are essential for their multiple cellular functions and are altered in disease. Tubulin carboxypeptidases (TCPs) responsible for detyrosination have remained elusive for 40 years (see the Perspective by Akhmanova and Maiato). Aillaud et al. identified vasohibins as enzymes that perform the TCP function and found that their small interacting partner SBVP was essential for their activity. Vasohibin/SVBP complexes were involved in neuron polarization and brain cortex development. The authors also developed an inhibitor targeting this family of enzymes. Using a completely different strategy, Nieuwenhuis et al. also showed that vasohibins can remove the C-terminal tyrosine of α-tubulin. Science, this issue p. 1448, p. 1453; see also p. 1381 The long-sought tubulin carboxypeptidases responsible for microtubule detyrosination have now been discovered. 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.

中文翻译：

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血管抑制素/SVBP 是调节神经元分化的微管蛋白羧肽酶 (TCP)

微管蛋白羧肽酶的特性揭示了 α-微管蛋白去酪氨酸化/酪氨酸化循环的酶在微管上创造了标志，这对其多种细胞功能至关重要，并在疾病中发生改变。40 年来，负责去酪氨酸化的微管蛋白羧肽酶 (TCP) 一直难以捉摸（参见 Akhmanova 和 Maiato 的观点）。艾洛等人。确定血管抑制素是执行 TCP 功能的酶，并发现它们的小相互作用伙伴 SBVP 对其活性至关重要。血管抑制素/SVBP 复合物参与神经元极化和大脑皮层发育。作者还开发了一种针对该酶家族的抑制剂。Nieuwenhuis 等人使用完全不同的策略。还表明血管抑制素可以去除 α-微管蛋白的 C 端酪氨酸。科学，这个问题 p。1448, 页。第1453章 另见第。1381 现在已经发现了负责微管去酪氨酸化的长期寻找的微管蛋白羧肽酶。α-微管蛋白的可逆去酪氨酸化对微管动力学和功能至关重要，缺陷与癌症、脑组织紊乱和心肌病有关。负责去酪氨酸化的微管蛋白酪氨酸羧肽酶 (TCP) 的身份仍不清楚。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大脑 TCP 是血管抑制素 1 (VASH1) 与小血管抑制素结合蛋白 (SVBP) 的复合物。VASH1 及其同源物 VASH2 当与 SVBP 复合时，在微管上表现出强大且特异性的 Tyr/Phe 羧肽酶活性。在培养的神经元中抑制血管抑制素或 SVBP 和/或添加抑制剂会降低去酪氨酸化的 α-微管蛋白水平并导致严重的分化缺陷。此外，血管抑制素的敲低会扰乱发育中的小鼠新皮质中的神经元迁移。因此，血管抑制素/SVBP 复合物代表了长期寻找的 TCP 酶。