Institute of Human Genetics (IGH), UMR9002 CNRS-University of Montpellier, 34094 Cedex 5, 141 Rue de la Cardonille, 34090 Montpellier, France.
Institute of Human Genetics (IGH), UMR9002 CNRS-University of Montpellier, 34094 Cedex 5, 141 Rue de la Cardonille, 34090 Montpellier, France.
Cell Rep. 2018 Dec 4;25(10):2866-2877.e5. doi: 10.1016/j.celrep.2018.10.095.
Tubulin glutamylation is a reversible posttranslational modification that accumulates on stable microtubules (MTs). While abnormally high levels of this modification lead to a number of disorders such as male sterility, retinal degeneration, and neurodegeneration, very little is known about the molecular mechanisms underlying the regulation of glutamylase activity. Here, we found that CSAP forms a complex with TTLL5, and we demonstrate that the two proteins regulate their reciprocal abundance. Moreover, we show that CSAP increases TTLL5-mediated glutamylation and identify the TTLL5-interacting domain. Deletion of this domain leads to complete loss of CSAP activating function without impacting its MT binding. Binding of CSAP to TTLL5 promotes relocalization of TTLL5 toward MTs. Finally, we show that CSAP binds and activates all of the remaining autonomously active TTLL glutamylases. As such, we present CSAP as a major regulator of tubulin glutamylation and associated functions.
微管谷氨酸化是一种可逆转的翻译后修饰,会在稳定的微管(MTs)上积累。虽然这种修饰的异常高水平会导致许多疾病,如雄性不育、视网膜变性和神经退行性变,但对于调节谷氨酸酶活性的分子机制知之甚少。在这里,我们发现 CSAP 与 TTLL5 形成复合物,并证明这两种蛋白调节它们的相对丰度。此外,我们表明 CSAP 增加了 TTLL5 介导的谷氨酸化,并确定了 TTLL5 相互作用的结构域。该结构域的缺失会导致 CSAP 激活功能完全丧失,而不会影响其与 MT 的结合。CSAP 与 TTLL5 的结合促进 TTLL5 向 MT 的重新定位。最后,我们表明 CSAP 结合并激活所有剩余的自主活性 TTLL 谷氨酸酶。因此,我们提出 CSAP 是微管谷氨酸化和相关功能的主要调节因子。