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

Abstract

Even after decades of research, a comprehensive mechanism that elucidates the underpinnings of signalling through the cell membrane is still elusive. Here, we address a simple question “how do 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 functional and structural 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 the weak cis interaction mediated ordered array of constitutively expressed signalling molecules not only support their ‘upright’ orientation but also bury their ligand-binding surface to avoid spurious signaling in the non-signalling resting state. With CD4, pMHCII, CD2 and TNFR1 as examples, we show that the observed association of molecules also correlate well with their functional role. Further, our model reconciles the long-standing controversies related to these molecules and appear to be generic enough to be applied to other signalling molecules

Cryptic association of B7‐2 molecules and its implication for clustering

“…Probably, transient and weak cis oligomerization or clustering of these molecules, at least in some cases, appears to provide the answer for the unsolved puzzle of how monomeric cell surface proteins stand in an “upright” orientation on the cell membrane. Such cis association has been proposed for some of the adhesion proteins and other proteins involved in immune signaling 38–40 . In particular, B7‐2 being a monomer in solution, either cis oligomerization or clustering appear to support its “upright” orientation and effective function on the cell surface.…”

“…Such cis association has been proposed for some of the adhesion proteins and other proteins involved in immune signaling. [38][39][40] In particular, B7-2 being a monomer in solution, either cis oligomerization or clustering appear to support its "upright" orientation and effective function on the cell surface.…”