Polyglutamylation is a reversible posttranslational modification that is catalyzed by enzymes of the tubulin tyrosine ligase-like (TTLL) family. Here, we found that TTLL11 generates a previously unknown type of polyglutamylation that is initiated by the addition of a glutamate residue to the free C-terminal carboxyl group of a substrate protein. TTLL11 efficiently polyglutamylates the Wnt signaling protein Dishevelled 3 (DVL3), thereby changing the interactome of DVL3. Polyglutamylation increases the capacity of DVL3 to get phosphorylated, to undergo phase separation, and to act in the noncanonical Wnt pathway. Both carboxy-terminal polyglutamylation and the resulting reduction in phase separation capacity of DVL3 can be reverted by the deglutamylating enzyme CCP6, demonstrating a causal relationship between TTLL11-mediated polyglutamylation and phase separation. Thus, C-terminal polyglutamylation represents a new type of posttranslational modification, broadening the range of proteins that can be modified by polyglutamylation and providing the first evidence that polyglutamylation can modulate protein phase separation.

中文翻译：

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羧基末端多谷氨酰化调节 Dishevelled 蛋白的信号转导和相分离。


聚谷氨酰化是一种可逆的翻译后修饰，由微管蛋白酪氨酸连接酶样 （TTLL） 家族的酶催化。在这里，我们发现 TTLL11 产生一种以前未知类型的多谷氨酰化，该多聚谷氨酰化是通过向底物蛋白的游离 C 末端羧基添加谷氨酸残基而引发的。TTLL11 有效地多谷氨酰化 Wnt 信号转导蛋白 Dishevelled 3 （DVL3），从而改变 DVL3 的相互作用组。聚谷氨酰化增加了 DVL3 被磷酸化、进行相分离和在非经典 Wnt 途径中起作用的能力。羧基末端聚谷氨酰化和由此导致的 DVL3 相分离能力降低都可以被去谷氨酰化酶 CCP6 逆转，证明了 TTLL11 介导的聚谷氨酰化和相分离之间存在因果关系。因此，C 端多谷氨酰化代表了一种新型的翻译后修饰，拓宽了可通过多聚谷氨酰化修饰的蛋白质范围，并提供了多谷氨酰化可以调节蛋白质相分离的第一个证据。