Even after decades of research, a comprehensive mechanism that elucidates the underpinnings of signaling through the cell membrane is still elusive. Here, we address a simple question- how does the ectodomain of a membrane-associated protein consisting of multiple domains and connected by flexible linkers stand upright on the membrane?. Our analysis based on large amount of available structural and functional data, looking for a pattern of association of these molecules in the crystal structures and with the concept that random things seldom repeat lead to a surprisingly interesting and consistent observation that (1) the weak cis-interaction mediated symmetric oligomerization of signaling molecules not only support their upright orientation but often bury their ligand-binding surface to avoid spurious signaling (2) the linkers connecting the domains are probably not flexible as presumed. This analysis provides a model for pre-liganded receptor supramolecular organization that resolves some of the mysteries unanswered by hypothesis such as lipid-rafts and fence and pickets. With CD4, pMHCII, CD2 and TNFR1 as examples, we show that the observed cis-association of molecules also correlate well with their functional role. Further, our analysis reconciles the long-standing controversies related to these molecules and appear to be generic enough to be applied to other signaling molecules.

中文翻译：

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膜相关蛋白的胞外域如何直立并发出稳定的信号

即使经过数十年的研究，阐明通过细胞膜进行信号传递的基础的全面机制仍然难以捉摸。在这里，我们解决一个简单的问题-由多个结构域组成并由柔性接头连接的膜相关蛋白的胞外域如何在膜上直立？我们的分析基于大量可用的结构和功能数据，寻找这些分子在晶体结构中的缔合模式，以及随机事物很少重复的概念导致令人惊讶的有趣且一致的观察结果，即（1）信号分子的弱顺式相互作用介导的对称低聚不仅支持其直立方向，但通常掩埋其配体结合表面以避免假信号（2）连接域的连接子可能不像假定的那样灵活。该分析为预先配位的受体超分子组织提供了模型，该模型解决了一些假设尚未解决的谜团，例如脂质筏，栅栏和栅栏。以CD4，pMHCII，CD2和TNFR1为例，我们显示观察到的分子的顺式缔合也与其功能作用密切相关。进一步，