Molecular interactions shaping the tetraspanin web

Abstract

To facilitate the myriad of different (signaling) processes that take place at the plasma membrane, cells depend on a high degree of membrane protein organization. Important mediators of this organization are tetraspanin proteins. Tetraspanins interact laterally among themselves and with partner proteins to control the spatial organization of membrane proteins in large networks called the tetraspanin web. The molecular interactions underlying the formation of the tetraspanin web were hitherto mainly described based on their resistance to different detergents, a classification which does not necessarily correlate with functionality in the living cell. To look at these interactions from a more physiological point of view, this review discusses tetraspanin interactions based on their function in the tetraspanin web: (1) intramolecular interactions supporting tetraspanin structure, (2) tetraspanin-tetraspanin interactions supporting web formation, (3) tetraspanin-partner interactions adding functional partners to the web and (4) cytosolic tetraspanin interactions regulating intracellular signaling. The recent publication of the first full-length tetraspanin crystal structure sheds new light on both the intra- and intermolecular tetraspanin interactions that shape the tetraspanin web. Furthermore, recent molecular dynamic modeling studies indicate that the binding strength between tetraspanins and between tetraspanins and their partners is the complex sum of both promiscuous and specific interactions. A deeper insight into this complex mixture of interactions is essential to our fundamental understanding of the tetraspanin web and its dynamics which constitute a basic building block of the cell surface.

Fibroblastic Reticular Cell Response to Dendritic Cells Requires Coordinated Activity of Podoplanin, CD44 and CD9

“…Tetraspanins are membrane-organizing proteins controlling expression of surface proteins via direct interaction or as chaperone during intracellular trafficking (46). Tetraspanins control a variety of cellular processes, including cell-cell interactions, cell migration, and signalling events (38,39). We find that tetraspanin CD82 is essential for podoplanin membrane localisation in FRCs; a more dramatic phenotype than reported in CD82 KO osteoclasts which also showed reduced podoplanin expression (42).…”

“…Protein surface expression can be controlled by intracellular trafficking, binding to membrane proteins for stabilisation, and by degradation. Tetraspanins are master-organisers of the plasma membrane, binding to and controlling expression of membrane proteins (38), but can also regulate protein trafficking (44). One candidate for controlling podoplanin expression is tetraspanin CD82 as it was recently reported that loss of CD82 in osteoclasts decreases podoplanin protein expression (45).…”

C-type lectin-like receptor 2 (CLEC-2)-dependent DC migration is controlled by tetraspanin CD37

“…SHP1 and CD37 have been shown to associate via the N-terminal ITIM-like domain of CD37 in chronic lymphocytic leukemia cells, which induced tumor cell death via negative regulation of AKT-mediated pro-apoptotic signaling (Lapalombella et al, 2012). The binding of cytoplasmic signaling proteins, like protein kinase C (PKC) (Zhang et al, 2001;Zuidscherwoude et al, 2017a), Rac1 (Tejera et al, 2013), and suppressor of cytokine signaling 3 (SOCS3) (de Winde et al, 2016) have been reported for different tetraspanins (also reviewed in (van Deventer et al, 2017)).…”

TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering

“…They share a common structure: four transmembrane domains (TMs), a small extracellular loop (SEL) and a large extracellular loop (LEL), and intracellular N and C termini (Berditchevski, 2001). Tetraspanins self-organize by homophilic interactions and accumulate in specialized mem-brane domains called tetraspanin-enriched microdomains (TEMs); this enables the concentration of other transmembrane proteins in segregated membrane domains (Charrin et al, 2002(Charrin et al, , 2009(Charrin et al, , 2003b(Charrin et al, , 2014Maecker et al, 1997;Boucheix and Rubinstein, 2001;van Deventer et al, 2017). Tetraspanins also bind cholesterol, an interaction thought to mediate their self-association (Charrin et al, 2003a).…”