The extremely conserved C-terminal region of reelin is not necessary for secretion but is required for efficient activation of downstream signaling
The extremely conserved C-terminal region of reelin is not necessary for secretion but is required for efficient activation of downstream signaling
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DOI：
10.1074/jbc.m702300200
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发表时间：
2007-07-13
影响因子：
4.8
通讯作者：
Hattori, Mitsuharu
中科院分区：
文献类型：
--
作者：
Nakano, Yoshimi;Kohno, Takao;Hattori, Mitsuharu
Reelin 是一种非常大的分泌糖蛋白，对于哺乳动物大脑的正确发育至关重要。它还与人类大脑的高级功能和疾病有关。然而，Reelin 的分泌是否受到调节以及 Reelin 如何传递信号仍然很大程度上未知。 Reelin 蛋白由 N 端 F-spondin 样结构域、Reelin 重复序列和短且高度碱性的 C 端区域 (CTR) 组成。 CTR的一级序列在除鱼类以外的脊椎动物中几乎完全保守，这表明了其重要性。关于 CTR 功能的一个普遍观点是，它是 Reelin 分泌所必需的，尽管这一点尚未得到证实。这里我们旨在阐明Reelin CTR的功能。删除大部分 CTR 或用不相关的氨基酸替换 CTR 均不会影响分泌效率，表明 CTR 并不是 Reelin 分泌所绝对需要的。我们还发现，没有 CTR 的 Reelin 突变体在激活皮质神经元下游信号传导方面的效力较差。尽管这些突变体能够与野生型Reelin一样有效地结合Reelin受体胞外域，但非常有趣的是，它们与带有Reelin受体的分离细胞膜或受体表达细胞（包括皮质神经元）的结合能力比野生型Reelin弱得多。因此，可以得出结论，Reelin 的 CTR 对其分泌来说并不是必需的，而是有效激活下游信号转导事件所必需的，大概是通过与细胞膜上未识别的“辅助受体”分子结合。
Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified "coreceptor" molecule(s) on the cell membrane.