The proprotein convertase PC5A and a metalloprotease are involved in the proteolytic processing of the neural adhesion molecule L1
The proprotein convertase PC5A and a metalloprotease are involved in the proteolytic processing of the neural adhesion molecule L1
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DOI：
10.1074/jbc.m208351200
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发表时间：
2003-03-21
影响因子：
4.8
通讯作者：
Schachner, M
中科院分区：
文献类型：
--
作者：
Kalus, I;Schnegelsberg, B;Schachner, M
跨膜和多结构域神经黏附分子L1在神经系统发育和成人神经系统中起着重要的功能作用。L1在细胞外域的两个不同的位置被蛋白质降解处理，导致不同片段的产生。在这份报告中，我们提出的证据是，原蛋白转换酶PC5A是在第三个纤维连接蛋白III型结构域中裂解L1的蛋白酶，而原蛋白转换酶Furin、PC1、PC2、PACE4和PC7在裂解L1方面不起作用。突变分析显示Arg(845)是产生N-末端140-kDa片段的切割位点。该片段存在于表达PC5A的海马体中，但在不表达PC5A的小脑中检测不到。140 kDa的L1片段与全长200 kDa的L1分子紧密结合。当被作用于全长L1的更靠近膜的位置的蛋白酶切割时，该复合体从膜上解离。这种蛋白水解性切割被金属蛋白酶抑制剂GM 6001抑制，而被钙调蛋白抑制剂增强。GM6001可抑制L1依赖的小脑神经元突起生长，提示金属蛋白酶对L1蛋白的降解作用参与了突起的生长。
The transmembrane and multidomain neural adhesion molecule L1 plays important functional roles in the developing and adult nervous system. L1 is proteolytically processed at two distinct sites within the extracellular domain, leading to the generation of different fragments. In this report, we present evidence that the proprotein convertase PC5A is the protease that cleaves L1 in the third fibronectin type III domain, whereas the proprotein convertases furin, PC1, PC2, PACE4, and PC7 are not effective in cleaving L1. Analysis of mutations revealed Arg(845) to be the site of cleavage generating the N-terminal 140-kDa fragment. This fragment was present in the hippocampus, which expresses PC5A, but was not detectable in the cerebellum, which does not express PC5A. The 140-kDa L1 fragment was found to be tightly associated with the full-length 200-kDa L1 molecule. The complex dissociated from the membrane upon cleavage by a protease acting at a more membrane-proximal site of full-length L1. This proteolytic cleavage was inhibited by the metalloprotease inhibitor GM 6001 and enhanced by a calmodulin inhibitor. L1-dependent neurite outgrowth of cerebellar neurons was inhibited by GM 6001, suggesting that proteolytic processing of L1 by a metalloprotease is involved in neurite outgrowth.