Abstract
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Few examples are added to depict the importance of EJ-linker in the main text In supplementary material, the example of TIGIT is added to support our hypothesis
Abbreviations
- IgV
- Immunoglobulin V-type domain
- IgC
- Immunoglobulin C-type domain