A Family of Protein-Deglutamylating Enzymes Associated with Neurodegeneration
A Family of Protein-Deglutamylating Enzymes Associated with Neurodegeneration
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DOI：
10.1016/j.cell.2010.10.014
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发表时间：
2010-11-12
期刊：
影响因子：
64.5
通讯作者：
Janke, Carsten
中科院分区：
文献类型：
--
作者：
Rogowski, Krzysztof;van Dijk, Juliette;Janke, Carsten
多聚谷氨酰化是一种翻译后修饰，在微管蛋白和其他蛋白质上产生谷氨酸侧链。虽然这种修饰已被证明是可逆的，但对催化脱谷氨酰化的酶知之甚少。在这里，我们描述了蛋白质脱谷氨酰的酶机制的胞质羧肽酶（CCP）家族的成员。三种酶（CCP 1，CCP 4和CCP 6）催化聚谷氨酸链的缩短，第四种酶（CCP 5）特异性地去除分支点谷氨酸。此外，CCP 1、CCP 4和CCP 6还从蛋白质的羧基末端去除基因编码的谷氨酸。因此，我们表明，这些酶将脱酪氨酸微管蛋白转化为Δ 2-微管蛋白，也修改其他底物，包括肌球蛋白轻链激酶1。我们进一步分析了浦肯野细胞变性（pcd）小鼠缺乏功能性CCP 1，并表明微管高谷氨酰胺化与神经变性直接相关。总之，我们的研究结果表明，控制微管蛋白上的聚谷氨酸侧链的长度对神经元的存活至关重要。
Polyglutamylation is a posttranslational modification that generates glutamate side chains on tubulins and other proteins. Although this modification has been shown to be reversible, little is known about the enzymes catalyzing deglutamylation. Here we describe the enzymatic mechanism of protein deglutamylation by members of the cytosolic carboxypeptidase (CCP) family. Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains and a fourth (CCP5) specifically removes the branching point glutamates. In addition, CCP1, CCP4, and CCP6 also remove gene-encoded glutamates from the carboxyl termini of proteins. Accordingly, we show that these enzymes convert detyrosinated tubulin into Delta 2-tubulin and also modify other substrates, including myosin light chain kinase 1. We further analyze Purkinje cell degeneration (pcd) mice that lack functional CCP1 and show that microtubule hyperglutamylation is directly linked to neurodegeneration. Taken together, our results reveal that controlling the length of the polyglutamate side chains on tubulin is critical for neuronal survival.