Role of Cytosolic Carboxypeptidase 5 in Neuronal Survival and Spermatogenesis.
Role of Cytosolic Carboxypeptidase 5 in Neuronal Survival and Spermatogenesis.
复制标题
胞质羧肽酶5在神经元存活和精子发生中的作用。
DOI：
10.1038/srep41428
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发表时间：
2017-01-27
影响因子：
4.6
通讯作者：
Morgan JI
中科院分区：
文献类型：
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作者：
Wu HY;Wei P;Morgan JI
蛋白质可能经历一种翻译后修饰-聚谷氨酰化，其中谷氨酸残基被酶促连接到蛋白质初级序列中的谷氨酸的γ-羧基，然后额外的谷氨酸通过α-羧基连接到不断增长的谷氨酸侧链上。NNA1(也称为CCP1)定义了一个由6个成员组成的胞浆羧基肽酶(CCP)家族，它代谢多聚谷氨酸侧链，其缺失会导致神经变性和男性不育。大多数CCP催化α-羧基连接的谷氨酸的水解，而CCP5独特地代谢γ-羧基连接的分支点谷氨酸。利用纯化的重组小鼠CCP5，我们证实它代谢合成底物的γ-羧基连接的谷氨酸和微管蛋白。尽管这一独特的特征及其在低等物种中不可或缺的功能，我们发现，与NNA1不同，CCP5对小鼠神经元的生存并不是必不可少的。CCP5缺乏确实会导致男性不育。然而，发生这种情况的机制与NNA1丢失的机制不同。相反，它的表型让人想起olt小鼠的不孕不育。我们的发现表明，无论是在神经系统还是在精子发生中，NNA1和CCP5都不是在同一条途径上协同工作。这是第一个关于CCP5在哺乳动物中的功能的研究。
Proteins may undergo a type of posttranslational modification – polyglutamylation, where a glutamate residue is enzymatically linked to the γ-carboxyl group of a glutamate in the primary sequence of proteins and additional glutamates are then sequentially added via α-carboxyl–linkages to the growing glutamate side chain. Nna1 (a.k.a. CCP1) defines the 6-member cytosolic carboxypeptidase (CCP) family that metabolizes polyglutamate side chain and its loss results in neurodegeneration and male infertility. Whereas most CCPs catalyze hydrolysis of α-carboxyl-linked glutamates, CCP5 uniquely metabolizes the γ-carboxyl linked, branch point glutamate. Using purified recombinant mouse CCP5, we confirmed that it metabolized γ-carboxyl-linked glutamate of synthetic substrates and tubulin. Despite this unique feature and its indispensible functions in lower species, we found that unlike Nna1, CCP5 is not essential for neuronal survival in mouse. CCP5 deficiency does cause male infertility. However, the mechanism by which this occurs is distinct from that of Nna1 loss. Instead, it is phenotypically reminiscent of the infertility of olt mice. Our findings suggest that Nna1 and CCP5 do not work coordinately in the same pathway in either the nervous system or spermatogenesis. This is the first study addressing the function of CCP5 in mammals.