TCDB is operated by the Saier Lab Bioinformatics Group

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).

References associated with 8.A.40 family:

Becirovic E., Nguyen ON., Paparizos C., Butz ES., Stern-Schneider G., Wolfrum U., Hauck SM., Ueffing M., Wahl-Schott C., Michalakis S. and Biel M. (2014). Peripherin-2 couples rhodopsin to the CNG channel in outer segments of rod photoreceptors. Hum Mol Genet. 23(22):5989-97. 24963162
Bjorkholm P., Ernst AM., Hacke M., Wieland F., Brugger B. and von Heijne G. (2014). Identification of novel sphingolipid-binding motifs in mammalian membrane proteins. Biochim Biophys Acta. 1838(8):2066-70. 24796501
Boavida, L.C., P. Qin, M. Broz, J.D. Becker, and S. McCormick. (2013). Arabidopsis tetraspanins are confined to discrete expression domains and cell types in reproductive tissues and form homo- and heterodimers when expressed in yeast. Plant Physiol. 163: 696-712. 23946353
Bui, S., J. Dancourt, and G. Lavieu. (2023). Virus-Free Method to Control and Enhance Extracellular Vesicle Cargo Loading and Delivery. ACS Appl Bio Mater 6: 1081-1091. 36781171
Charrin, S., S. Jouannet, C. Boucheix, and E. Rubinstein. (2014). Tetraspanins at a glance. J Cell Sci 127: 3641-3648. 25128561
Chicote, J.U., R. DeSalle, J. Segarra, T.T. Sun, and A. García-España. (2017). The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor. PLoS One 12: e0170196. 28099513
Cocquerel, L., C.C. Kuo, J. Dubuisson, and S. Levy. (2003). CD81-dependent binding of hepatitis C virus E1E2 heterodimers. J. Virol. 77: 10677-10683. 12970454
Curley, N., D. Levy, M.A. Do, A. Brown, Z. Stickney, G. Marriott, and B. Lu. (2020). Sequential deletion of CD63 identifies topologically distinct scaffolds for surface engineering of exosomes in living human cells. Nanoscale 12: 12014-12026. 32463402
Dickerson, M.T., P.K. Dadi, R.B. Butterworth, A.Y. Nakhe, S.M. Graff, K.E. Zaborska, C.M. Schaub, and D.A. Jacobson. (2020). Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls pancreatic β-cell insulin secretion. J. Physiol. [Epub: Ahead of Print] 32790176
Farquhar, M.J., H.J. Harris, and J.A. McKeating. (2011). Hepatitis C virus entry and the tetraspanin CD81. Biochem Soc Trans 39: 532-536. 21428934
Goetzl, E.J., V.H. Srihari, M. Mustapic, D. Kapogiannis, and G.R. Heninger. (2022). Abnormal levels of mitochondrial Ca channel proteins in plasma neuron-derived extracellular vesicles of early schizophrenia. FASEB J. 36: e22466. 35867070
Haining, E.J., A.L. Matthews, P.J. Noy, H.M. Romanska, H.J. Harris, J. Pike, M. Morowski, R.L. Gavin, J. Yang, P.E. Milhiet, F. Berditchevski, B. Nieswandt, N.S. Poulter, S.P. Watson, and M.G. Tomlinson. (2017). Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation. Platelets 28: 629-642. 28032533
Haining, E.J., J. Yang, R.L. Bailey, K. Khan, R. Collier, S. Tsai, S.P. Watson, J. Frampton, P. Garcia, and M.G. Tomlinson. (2012). The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression. J. Biol. Chem. 287: 39753-39765. 23035126
Halova, I. and P. Draber. (2016). Tetraspanins and Transmembrane Adaptor Proteins As Plasma Membrane Organizers-Mast Cell Case. Front Cell Dev Biol 4: 43. 27243007
Hálová, I., L. Dráberová, M. Bambousková, M. Machyna, L. Stegurová, D. Smrz, and P. Dráber. (2013). Cross-talk between tetraspanin CD9 and transmembrane adaptor protein non-T cell activation linker (NTAL) in mast cell activation and chemotaxis. J. Biol. Chem. 288: 9801-9814. 23443658
Hemler, M.E. (2005). Tetraspanin functions and associated microdomains. Nat Rev Mol. Cell Biol. 6: 801-811. 16314869
Higginbottom, A., Y. Takahashi, L. Bolling, S.A. Coonrod, J.M. White, L.J. Partridge, and P.N. Monk. (2003). Structural requirements for the inhibitory action of the CD9 large extracellular domain in sperm/oocyte binding and fusion. Biochem. Biophys. Res. Commun. 311: 208-214. 14575715
Higgins, C.B., J.A. Adams, M.H. Ward, Z.J. Greenberg, M. Milewska, J. Sun, Y. Zhang, L. Chiquetto Paracatu, Q. Dong, S. Ballentine, W. Li, I. Wandzik, L.G. Schuettpelz, and B.J. DeBosch. (2022). The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes. J. Biol. Chem. 299: 102835. [Epub: Ahead of Print] 36581203
Ikeyama, S., M. Koyama, M. Yamaoko, R. Sasada, and M. Miyake. (1993). Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med 177: 1231-1237. 8478605
Ipinmoroti, A.O., R. Pandit, B.J. Crenshaw, B. Sims, and Q.L. Matthews. (2023). Selective pharmacological inhibition alters human carcinoma lung cell-derived extracellular vesicle formation. Heliyon 9: e16655. 37303541
Jankovicova, J., M. Frolikova, N. Sebkova, M. Simon, P. Cupperova, D. Lipcseyova, K. Michalkova, L. Horovska, R. Sedlacek, P. Stopka, J. Antalikova, and K. Dvorakova-Hortova. (2016). Characterization of tetraspanin protein CD81 in mouse spermatozoa and bovine gametes. Reproduction. [Epub: Ahead of Print] 27679865
Jouannet, S., J. Saint-Pol, L. Fernandez, V. Nguyen, S. Charrin, C. Boucheix, C. Brou, P.E. Milhiet, and E. Rubinstein. (2016). TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization. Cell Mol Life Sci 73: 1895-1915. 26686862
Lacinova, L., R.T. Mallmann, B. Jurkovičová-Tarabová, and N. Klugbauer. (2020). Modulation of voltage-gated Ca2.2 Ca channels by newly identified interaction partners. Channels (Austin). [Epub: Ahead of Print] 33006503
Lafleur, M.A., D. Xu, and M.E. Hemler. (2009). Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis. Mol. Biol. Cell 20: 2030-2040. 19211836
Lee, S.Y., J.M. Kim, S.Y. Cho, H.S. Kim, H.S. Shin, J.Y. Jeon, R. Kausar, S.Y. Jeong, Y.S. Lee, and M.A. Lee. (2014). TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. Biochem. J. 459: 565-576. 24635319
Mallmann, R.T., T. Wilmes, L. Lichvarova, A. Bührer, B. Lohmüller, J. Castonguay, L. Lacinova, and N. Klugbauer. (2013). Tetraspanin-13 modulates voltage-gated CaV2.2 Ca2+ channels. Sci Rep 3: 1777. 23648579
Matthews, A.L., J. Szyroka, R. Collier, P.J. Noy, and M.G. Tomlinson. (2017). Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins. Biochem Soc Trans 45: 719-730. 28620033
Matthews, A.L., P.J. Noy, J.S. Reyat, and M.G. Tomlinson. (2016). Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets 1-9. [Epub: Ahead of Print] 27256961
McLaughlin, K., S. Acreman, S. Nawaz, J. Cutteridge, A. Clark, J.G. Knudsen, G. Denwood, A.F. Spigelman, J.E. Manning Fox, S.P. Singh, P.E. MacDonald, B. Hastoy, and Q. Zhang. (2022). Loss of tetraspanin-7 expression reduces pancreatic β-cell exocytosis Ca sensitivity but has limited effect on systemic metabolism. Diabet Med 39: e14984. 36264270
McLaughlin, K.A., C.C. Richardson, A. Ravishankar, C. Brigatti, D. Liberati, V. Lampasona, L. Piemonti, D. Morgan, R.G. Feltbower, and M.R. Christie. (2016). Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes. Diabetes. [Epub: Ahead of Print] 26953162
Nakazawa, Y., S. Sato, M. Naito, Y. Kato, K. Mishima, H. Arai, T. Tsuruo, and N. Fujita. (2008). Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood 112: 1730-1739. 18541721
Noy, P.J., J. Yang, J.S. Reyat, A.L. Matthews, A.E. Charlton, J. Furmston, D.A. Rogers, G.E. Rainger, and M.G. Tomlinson. (2016). TspanC8 Tetraspanins and A Disintegrin and Metalloprotease 10 (ADAM10) Interact via Their Extracellular Regions: EVIDENCE FOR DISTINCT BINDING MECHANISMS FOR DIFFERENT TspanC8 PROTEINS. J. Biol. Chem. 291: 3145-3157. 26668317
Noy, P.J., R.L. Gavin, D. Colombo, E.J. Haining, J.S. Reyat, H. Payne, I. Thielmann, A.B. Lokman, G. Neag, J. Yang, T. Lloyd, N. Harrison, V.L. Heath, C. Gardiner, K.M. Whitworth, J. Robinson, C.Z. Koo, A. Di Maio, P. Harrison, S.P. Lee, F. Michelangeli, N. Kalia, G.E. Rainger, B. Nieswandt, A. Brill, S.P. Watson, and M.G. Tomlinson. (2018). Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells. Haematologica. [Epub: Ahead of Print] 30573509
Parra-Aguilar, T.J., L.G. Sarmiento-López, O. Santana, J.E. Olivares, E. Pascual-Morales, S. Jiménez-Jiménez, A. Quero-Hostos, J. Palacios-Martínez, A.I. Chávez-Martínez, and L. Cárdenas. (2023). TETRASPANIN 8-1 from plays a key role during mutualistic interactions. Front Plant Sci 14: 1152493. 37465390
Pols, M.S. and J. Klumperman. (2009). Trafficking and function of the tetraspanin CD63. Exp Cell Res 315: 1584-1592. 18930046
Rawat, U.B. and M.B. Rao. (1996). Purification, kinetic characterization and involvement of tryptophan residue at the NADPH binding site of xylose reductase from Neurospora crassa. Biochim. Biophys. Acta. 1293: 222-230. 8620033
Sabetian, S., M.S. Shamsir, and M. Abu Naser. (2014). Functional features and protein network of human sperm-egg interaction. Syst Biol Reprod Med 60: 329-337. 25222562
Seipold, L. and P. Saftig. (2016). The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein. Front Mol Neurosci 9: 149. 28066176
Susa, K.J., A.C. Kruse, and S.C. Blacklow. (2023). Tetraspanins: structure, dynamics, and principles of partner-protein recognition. Trends Cell Biol. [Epub: Ahead of Print] 37783654
Takeda, Y., I. Tachibana, K. Miyado, M. Kobayashi, T. Miyazaki, T. Funakoshi, H. Kimura, H. Yamane, Y. Saito, H. Goto, T. Yoneda, M. Yoshida, T. Kumagai, T. Osaki, S. Hayashi, I. Kawase, and E. Mekada. (2003). Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes. J. Cell Biol. 161: 945-956. 12796480
Tu, L., X.P. Kong, T.T. Sun, and G. Kreibich. (2006). Integrity of all four transmembrane domains of the tetraspanin uroplakin Ib is required for its exit from the ER. J Cell Sci 119: 5077-5086. 17158912
van Niel, G., S. Charrin, S. Simoes, M. Romao, L. Rochin, P. Saftig, M.S. Marks, E. Rubinstein, and G. Raposo. (2011). The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell 21: 708-721. 21962903
van Zelm, M.C., J. Smet, B. Adams, F. Mascart, L. Schandené, F. Janssen, A. Ferster, C.C. Kuo, S. Levy, J.J. van Dongen, and M. van der Burg. (2010). CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest 120: 1265-1274. 20237408
Xu, D., C. Sharma, and M.E. Hemler. (2009). Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23: 3674-3681. 19587294
Yang, Y.G., I.N. Sari, M.F. Zia, S.R. Lee, S.J. Song, and H.Y. Kwon. (2016). Tetraspanins: Spanning from Solid Tumors to Hematologic Malignancies. Exp Hematol. [Epub: Ahead of Print] 26930362
Yeh, H.Y. and P.H. Klesius. (2009). Channel catfish, Ictalurus punctatus Rafinesque 1818, tetraspanin membrane protein family: characterization and expression analysis of CD81 cDNA. Vet Immunol Immunopathol 128: 431-436. 19131118
Yeh, H.Y. and P.H. Klesius. (2010). Channel catfish (Ictalurus punctatus Rafinesque, 1818) tetraspanin membrane protein family: identification, characterization and expression analysis of CD63 cDNA. Vet Immunol Immunopathol 133: 302-308. 19726089
Yeh, H.Y. and P.H. Klesius. (2012). Channel catfish, Ictalurus punctatus (Rafinesque), tetraspanin membrane protein family: identification, characterization and phylogenetic analysis of tetraspanin 3 and tetraspanin 7 (CD231) transcripts. Fish Physiol Biochem 38: 1553-1563. 22547004