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8.A.40 The Tetraspanin (Tetraspanin) Family

This 4TMS protein superfamily includes CD81 (TAPA-1; tetraspannin-28), a co-receptor of hepatitis C virus (HCV) in a heterodimer with SR-B1 (TC#9.B.39.1.3) (Cocquerel et al. 2003) as well as CD151 (Tetraspannin-24). Loss yields poor B-cell development and antibody deficiency (van Zelm et al. 2010). This protein functions in signal transmission. Defects are the cause of immunodeficiency common variable type 6 (CVID6) and prevent efficient antibody secretion.  Tetraspanins regulate the trafficking and function of partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system (Charrin et al. 2014).  Sperm-egg interaction and fusion would not happen in mammals without the interaction of tetraspanin superfamily members including protein CD81 (Jankovicova et al. 2016).

Tetraspanins may be involved in cell proliferation and motility. Defects of TSPAN7 in humans result in mental retardation, called x-linked type 58 (MRX58) (Hemler 2005). Orthologues of several human tetraspanins have been studied in other organisms (Yeh and Klesius 2012).  One such protein, CD63, is involved in trafficking and transport regulation (Pols and Klumperman 2009). In addition (Susa et al. 2023):


  • Tetraspanins regulate signal transduction by interacting with partner proteins belonging to different protein families, including extracellular enzymes, integrins, members of the immunoglobulin superfamily, and intracellular signaling proteins.

  • Structures of full-length tetraspanins have revealed a common overall architecture, with a cone-shaped transmembrane (TM) domain containing an intramembrane binding pocket. This pocket can bind lipids, which appear to modulate tetraspanin function.

  • Many tetraspanins are conformationally dynamic, existing in at least two states with distinct TM conformations and ectodomain orientations.

  • The molecular association of a tetraspanin with its partner can be mediated through the large extracellular loop (EC2 domain) and/or the TM domain. The dependency for each region differs based on the bound partner (Susa et al. 2023).

TSPAN-13 specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel and accelerates the voltage-dependent activation and inactivation of Ba2+ currents through Cav2.2 (TC# 1.A.1.11.9). It may regulate Cav2.2 Ca2+ channel activity in defined synaptic membrane compartments and thereby influence transmitter release (Mallmann et al. 2013).

Disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions of over 40 different transmembrane target proteins, including Notch and amyloid precursor protein in humans (Haining et al. 2012). ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which comprise a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane ''partner'' proteins (Noy et al. 2016). This is achieved by specific tetraspanin-partner interactions. ADAM10 interacts with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the TspanC8 subgroup of tetraspanins, all six of which promote ADAM10 maturation (Jouannet et al. 2016). Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. TspanC8 tetraspanins are thus essential regulators of ADAM10 maturation and trafficking to the cell surface (Matthews et al. 2016). The biology of tetraspanins and how they interact with APP processing pathways have been reviewed (Seipold and Saftig 2016).

There are 33 mammalian tetraspanins, most of which interact with and regulate specific partner proteins within membrane nanodomains, some of which are described above. Tetraspanins appear to have a cone-shaped structure with a cholesterol-binding cavity, which may enable tetraspanins to undergo cholesterol-regulated conformational changes. The TspanC8 subgroup of tetraspanins, including Tspan5, 10, 14, 15, 17 and 33, regulate Adam10. Thus, TspanC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation. Different TspanC8s localise ADAM10 to different subcellular localisations and may cause ADAM10 to adopt distinct conformations with cleavage of distinct substrates. Matthews et al. 2017 proposed that ADAM10 should be regarded as six different scissor proteins depending on its interacting TspanC8.

β-cell TSPAN-7 regulates Ca2+ handling and hormone secretion. Dickerson et al. 2020 found that TSPAN-7 reduces beta-cell glucose-stimulated Ca2+ entry, slows Ca2+ oscillation frequency, and decreases glucose-stimulated insulin secretion. TSPAN-7 controls β-cell function through a direct interaction with L-type voltage-dependent Ca2+ channels (CaV 1.2 and CaV 1.3), which reduces channel Ca2+ conductance. TSPAN-7 slows activation of CaV 1.2 and accelerates recovery from voltage-dependent inactivation; TSPAN-7 also slows CaV 1.3 inactivation kinetics. These findings strongly implicate TSPAN-7 as a key regulator in determining the setpoint of glucose-stimulated Ca(2+) influx and insulin secretion (Dickerson et al. 2020).

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