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). 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). 

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.



This family belongs to the .

 

References:

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.

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.

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.

Charrin, S., S. Jouannet, C. Boucheix, and E. Rubinstein. (2014). Tetraspanins at a glance. J Cell Sci 127: 3641-3648.

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.

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.

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.

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.

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.

Halova, I. and P. Draber. (2016). Tetraspanins and Transmembrane Adaptor Proteins As Plasma Membrane Organizers-Mast Cell Case. Front Cell Dev Biol 4: 43.

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.

Hemler, M.E. (2005). Tetraspanin functions and associated microdomains. Nat Rev Mol. Cell Biol. 6: 801-811.

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]

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.

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.

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.

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.

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.

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]

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]

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.

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]

Pols, M.S. and J. Klumperman. (2009). Trafficking and function of the tetraspanin CD63. Exp Cell Res 315: 1584-1592.

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.

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.

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.

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.

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.

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.

Xu, D., C. Sharma, and M.E. Hemler. (2009). Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23: 3674-3681.

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]

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.

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.

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.

Examples:

TC#NameOrganismal TypeExample
8.A.40.1.1

CD81 (TAPA1, Tspan28) co-receptor of Hepatitis C Virus (HCV); forms a heterodimer with SR-B1 (TC#9.B.39.1.3). Defects cause CVID6. Plays a role in hepatitis C entry via endocytosis (Farquhar et al., 2011).  Plays roles in immune and other physiological functions (Yeh and Klesius 2009).  Sperm-egg interaction and fusion would not happen in mammals without tetraspanin superfamily members including protein CD81 (Jankovicova et al. 2016).

Animals

CD81 of Homo sapiens (P60033)

 
8.A.40.1.10

Tetraspanin 10 (Haining et al., 2012).

Animals

Tetraspanin 10 of Homo sapiens

 
8.A.40.1.11

Tetraspanin 33; penumbra (Haining et al. 2012).

Animals

Penumbra of Homo sapiens

 
8.A.40.1.12

Catfish CD63 antigen tetraspanin of 237 aas (Yeh and Klesius 2010).  Involved in trafficking and transport regulation (Pols and Klumperman 2009).

Animals

CD63 of Ictalurus punctatus (Channel catfish) (Silurus punctatus)

 
8.A.40.1.13

Uncharacterized protein of 221 aas and 4 TMSs.

Animals (insects)

UP of Danaus plexippus

 
8.A.40.1.14

Uncharacterized protein of 219 aas and 4 TMSs.

Algae

UP of Galdieria sulphuraria

 
8.A.40.1.15

The tetraspan 24 protein, TSPAN24 or CD151 of 254 aas and 4 TMSs.  Essential for the proper assembly of the glomerular and tubular basement membranes in kidney.  Also functions in egg-sperm interactions, possibly in cell-cell fusion, where oocyte CD151 interacts with CD49 in the sperm (Sabetian et al. 2014).

Animals

CD151 of Homo sapiens

 
8.A.40.1.16

Tetraspanin-3 (TSPAN3) of 253 aas and 4 TMSs in a 3+ 1 arrangement.  Plays a role in myeloid leukemia and other cancers (Yang et al. 2016).

TSPAN3 of Homo sapiens

 
8.A.40.1.17

Tetraspannin 15, TSPAN15 of 294 aas and 4 TMSs.  Interacts with and regulates the targetting and activity of the sheddase, ADAM10 (TC# 8.A.77) (Prox et al. 2012).

TSPAN15 of Homo sapiens

 
8.A.40.1.18

Human Leukocyte surface antigen CD53 of 219 aas and 4 TMSs (Halova and Draber 2016). 

CD53 of Homo sapiens

 
8.A.40.1.19

Antigen CD63 of 238 aas and 4 TMSs.  Functions as cell surface receptor, and plays a role in the activation of cellular signaling cascades.  Plays a role in intracellular vesicular transport processes, and is required for normal trafficking that is essential for the development and maturation of melanocytes (van Niel et al. 2011; Lee et al. 2014).

CD63 of Homo sapiens

 
8.A.40.1.2

Tetraspanin-7 (Tspan-7; TALLA1; MXS1; TM4SF2) (Hemler, 2005). Defects in humans result in mental retardation, called x-linked type 58 (MRX58) (Hemler, 2005).  Contains sphingolipid binding motifs (Björkholm et al. 2014).  Tspan-7 is the target of autoantibodies and type I diabetes (McLaughlin et al. 2016).

Animals

Tspan-7 of Homo sapiens (P41732)

 
8.A.40.1.20

Tetraspanin-12, Tspan12, of 305 aas and 4 TMSs.  Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs (Lafleur et al. 2009). Activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP) (Xu et al. 2009).  The biology of tetraspanins and how they interact with APP processing pathways have been reviewed (Seipold and Saftig 2016).

Tspan12 of Homo sapiens

 
8.A.40.1.21

Tetraspanin14 (Tspan14) of 270 aas and 4 TMSs. Interacts with disintegrin and metalloprotease 10 (ADAM10), a ubiquitously expressed transmembranemetalloprotease that cleaves the extracellular regions from its transmembrane substrates (Noy et al. 2016). ADAM10 is essential for embryonic development and is implicated in cancer, Alzheimer's disease, and inflammatory diseases. The tetraspanins are a superfamily of 33 four-transmembrane proteins in mammals, of which the TspanC8 subgroup (Tspan5, 10, 14, 15, 17, and 33) promote ADAM10 intracellular trafficking and enzymatic maturation (Jouannet et al. 2016).

TspanC8 of Homo sapiens

 
8.A.40.1.22

Tetraspan-9, Tspan9, of 239 aas and 4 TMSs.  Plays a role in aggregation and secretion induced by the platelet collagen receptor, GPVI, despite normal surface GPVI expression levels. This is because Tspan9 plays a role in platelet activation by regulating GPVI membrane dynamics (Haining et al. 2017).

Tspan9 of Homo sapiens

 
8.A.40.1.23

Tetraspannin, Tspan18 of 248 aas and 4 TMSs in a 3 + 1 arrangement.  It is a regulator of Orai1, a store-operated Ca2+ channels in the plasma membrane which is critical to cell function. Orai1 loss causes severe immunodeficiency and developmental defects (Noy et al. 2018).

Tspan18 of Homo sapiens

 
8.A.40.1.3

Peripherin-2 of 346 aas and 4 TMSs; Rod outer segment membrane protein; RDS; PRDH2. Causes retenal degeneration.  Links rhodopsin (TC# 9.A.14.1.2) to a cyclic nucleotide-dependent channel (TC# 1.A.1.5.3) in the outer segments of rod photoreceptors.  The G266D retinitis pigmentosa mutation in TMS4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014).

Animals

Peripherin-2 of Homo sapiens (P23942)

 
8.A.40.1.4

Late bloomer; facilitates synapse and cell junction formation 

Animals

Late bloomer of Drosophila melanogaster (Q24188)

 
8.A.40.1.5

CD63 antigen-like tetraspanin.  Involved in trafficking and transport regulation (Pols and Klumperman 2009).

Animals

CD63-like protein of Schistosoma mansoni (G4VD44)

 
8.A.40.1.6

Tetraspannin, Tsp3A; involved in phagocytosis; engulfment.

Animals

Tsp3A of Drosophila melanogaster

 
8.A.40.1.7

 

Tetraspannin, Tsp42Fi

Animals

Tsp42Fi of Drosophila melanogaster

 
8.A.40.1.8

Tretraspanin-13.  TSPAN-13 specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the CaV2.2 α-subunit channel and accelerates the voltage-dependent activation and inactivation of the Ba2+ current through CaV2.2.  TSPAN-13 may regulate CaV2.2 Ca2+ channel activity in defined synaptic membrane compartments and thereby influences transmitter release (23648579).

Animals

Tetraspanin-13 of Mus musculus

 
8.A.40.1.9

Tetraspanin 29 (TSPAN29; CD9 antigen; GIG2; leucocyte antigen MIC3) of 228 aas and 4 TMSs.  Plays a role in mast cell chemotaxis (Hálová et al. 2013).  Also required for egg-sperm interactions during cell-cell fusion (Sabetian et al. 2014). 

Animals

Tetraspanin 29 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.2.1

Tetraspanin

Fungi

Tetraspanin of Neurospora crassa (Q8J0D3)

 
8.A.40.2.2

Tetraspanin 

Fungi

Tetraspanin of Melampsora laricipopulina (F4S576)

 
8.A.40.2.3

Similar to tetraspanin

Fungi

Tetraspanin homologue of Leptosphaeria maculans

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.3.1

Tetraspanin family protein

Ciliates

Tetraspanin of Tetrahymena thermophila

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.4.1

Putative senescence-associated protein

Plants

Putative senescence-associated protein of Oryza sativa

 
8.A.40.4.2

Tetraspanin-10 of 284 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-18 of Arabidopsis thaliana

 
8.A.40.4.3

Tetraspanin-16 of 248 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-16 of Arabidopsis thaliana

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.5.1

Tetraspanin-20 of 281 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-20 of Arabidopsis thaliana

 
8.A.40.5.2

Tetraspanin 18 of 270 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-18 of Arabidopsis thaliana

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.6.1

Tetraspanin-14 of 260 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-14 of Arabidopsis thaliana

 
8.A.40.6.2

Tetraspanin-15 of 317 aas and 4 TMSs (Boavida et al. 2013).

Plants

Tetraspanin-15 of Arabidopsis thaliana

 
Examples:

TC#NameOrganismal TypeExample
8.A.40.7.1

Uroplakin 1a (UPK1A or TSPAN21) of 258 aas and 4 TMSs in a 3 + 1 arrangement.  Component of the asymmetric unit membrane (AUM), a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play a role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells (Chicote et al. 2017).

UPK1A of Homo sapiens

 
8.A.40.7.2

Uroplakin 1b, UPK1B of 260 aas and 4 TMSs in a 3 + 1 arrangement.  Like UPK1A, it may be a component of the asymmetric unit membrane (AUM), a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells (Chicote et al. 2017). Proper formation of helical bundles consisting of the 4 tetraspanin TMSs seems to be a prerequisite for UPIb to exit from the ER into the plasma membrane (Tu et al. 2006).

UKB1B of Homo sapiens