Characterization of sequential N-cadherin cleavage by ADAM10 and PS1
Characterization of sequential N-cadherin cleavage by ADAM10 and PS1
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DOI：
10.1016/j.neulet.2006.04.018
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发表时间：
2006-07-24
影响因子：
2.5
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Uemura, Kengo;Kihara, Takeshi;Shimohama, Shun
N-钙粘蛋白是海马兴奋性突触接触所必需的。在突触接触位点，它与早老素1（PS1）和β-连环蛋白形成复合物。N-钙粘蛋白在响应NMDA受体刺激时被ADAM 10切割，在神经元中产生膜片段Ncad/CTF 1。NMDA受体刺激也增强PS1/γ-分泌酶介导的N-钙粘蛋白裂解。为了表征ADAM 10和PS1介导的切割的调节机制，我们首先通过产生切割缺陷的N-钙粘蛋白突变体来鉴定ADAM 10和PS1/γ-分泌酶对N-钙粘蛋白的精确切割位点。接下来，我们发现，由ADAM 10的N-钙粘蛋白的胞外域脱落是响应钙内流的主要调节步骤，并且它是随后的PS1/γ-分泌酶介导的N-钙粘蛋白的ε-切割所必需的，这是产生胞质片段Ncad/CTF 2的组成性过程。由于N-cadherin对突触的结构和功能包括长时程增强都是必不可少的，因此N-cadherin的蛋白水解事件应该会影响突触的粘附行为，从而参与学习和记忆。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
N-cadherin is essential for excitatory synaptic contact in the hippocampus. At the sites of synaptic contact, it forms a complex with Presenilin 1 (PS1) and beta-catenin. N-cadherin is cleaved by ADAM 10 in response to NMDA receptor stimulation, producing a membrane fragment Ncad/CTF1 in neurons. NMDA receptor stimulation also enhances PS1/gamma-secretase-mediated cleavage of N-cadherin. To characterize the regulatory mechanisms of the ADAM10 and PSI-mediated cleavages, we first identified the precise cleavage sites of N-cadherin by ADAM10 and PS1/gamma-secretase by producing cleavage-deficient N-cadherin mutants. Next, we found that ectodomain shedding of N-cadherin by ADAM 10 is a primary regulatory step in response to calcium influx, and that it is required for the subsequent PS1/gamma-secretase-mediated epsilon-cleavage of N-cadherin, which is a constitutive process to yield a cytoplasmic fragment, Ncad/CTF2. Since N-cadherin is essential for the structure and function of synapses including the long-term potentiation, those proteolytic events of N-cadherin should affect the adhesive behavior of the synapses, thereby taking part in learning and memory. (c) 2006 Elsevier Ireland Ltd. All rights reserved.