NEURAL CELL-ADHESION MOLECULE - STRUCTURE, IMMUNOGLOBULIN-LIKE DOMAINS, CELL-SURFACE MODULATION, AND ALTERNATIVE RNA SPLICING
NEURAL CELL-ADHESION MOLECULE - STRUCTURE, IMMUNOGLOBULIN-LIKE DOMAINS, CELL-SURFACE MODULATION, AND ALTERNATIVE RNA SPLICING
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DOI：
10.1126/science.3576199
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发表时间：
1987-05-15
期刊：
影响因子：
56.9
通讯作者：
EDELMAN, GM
中科院分区：
文献类型：
--
作者：
CUNNINGHAM, BA;HEMPERLY, JJ;EDELMAN, GM
神经细胞黏附分子N-CAM出现在早期胚胎细胞上，在形态发生部位的细胞团及其边界的形成中起重要作用。在发育后期，它在各种分化的组织中被发现，是一种主要的CAM，介导神经元之间以及神经元与肌肉之间的黏附。为了解N-CAM的功能提供分子基础，通过对互补DNA克隆的分析，确定了N-CAM的三个主要多肽的完整氨基酸序列及其信使RNA的大部分非编码序列，并通过选定的CNBR片段和蛋白水解性片段的氨基酸序列进行了验证。每个N-CAM多肽的胞外区包括5个相邻的片段，它们在序列上彼此同源，并与免疫球蛋白超家族成员同源，这表明免疫球蛋白样结构域之间的相互作用构成了N-CAM同源结合的基础。虽然这三个多肽在膜相关和胞质结构域上不同，但在结合位点所在的这个胞外区(682个氨基酸)中，它们的氨基酸序列似乎是相同的。因此，N-CAM活性的变化不会通过改变结合的特异性的氨基酸序列的变化而发生。相反，调控是通过细胞表面调节事件来实现的，这些事件改变了N-CAM的亲和力、流行率、迁移率和表面分布。调控的一个主要机制是选择性的RNA剪接，导致N-CAM具有不同的细胞质结构域，与细胞膜有不同的相互作用。这种调节机制可能将N-CAM结合功能与模式胚胎发育过程中的其他初级细胞过程联系起来。
The neural cell adhesion molecule, N-CAM, appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis. Later in development it is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle. To provide a molecular basis for understanding N-CAM function, the complete amino acid sequences of the three major polypeptides of N-CAM and most of the noncoding sequences of their messenger RNA's were determined from the analysis of complementary DNA clones and were verified by amino acid sequences of selected CNBr fragments and proteolytic fragments. The extracellular region of each N-CAM polypeptide includes five contiguous segments that are homologous in sequence to each other and to members of the immunoglobulin superfamily, suggesting that interactions among immunoglobulin-like domains form the basis for N-CAM homophilic binding. Although different in their membrane-associated and cytoplasmic domains, the amino acid sequences of the three polypeptides appear to be identical throughout this extracellular region (682 amino acids) where the binding site is located. Variations in N-CAM activity thus do not occur by changes in the amino acid sequence that alter the specificity of binding. Instead, regulation is achieved by cell surface modulation events that alter N-CAM affinity, prevalence, mobility, and distribution on the surface. A major mechanism for modulation is alternative RNA splicing resulting in N-CAM's with different cytoplasmic domains that differentially interact with the cell membrane. Such regulatory mechanisms may link N-CAM binding function with other primary cellular processes during the embryonic development of pattern.