How does an ectodomain of membrane-associated proteins stand upright and exert robust signal

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.