8.A.9 The rBAT Transport Accessory Protein (rBAT) Family

The rBAT (related to b0,+ amino acid transport) proteins have been sequenced from a variety of animals and when expressed in frog oocytes, they cause induction of cationic and neutral amino acid uptake. The activities enhanced depend on the cell type into which the mRNA is injected. The rBAT and homologous 4F2hc proteins, which like rBAT proteins, stimulate amino acid transport proteins, have 520-690 amino acids and are glycoproteins with a putative hydrophobic transmembrane spanner (TMS) and possibly as many as three additional amphipathic TMSs. These proteins are homologous to maltases, α-glucosidases and trehalose 6-P hydrolases. They are probably auxiliary proteins that are required for insertion of or stimulation of the activities of various porters, including some of those of the APC family (TC# 2.A.3). Some of these homologues have been shown to associate with various amino acid porters to form heterodimeric or heterotetrameric protein complexes.

The 4F2hc protein is called the cell surface antigen heavy chain, lymphocyte activation antigen and CD98. It activates the cystine/glutamate antiporter (2.A.3.8.5) and other amino acid transporters (Sato et al., 2005). CD98 in intestinal epithelia is an oligomeric and multifunctional protein (Yan et al., 2008).

rBAT dictates oligomerization of heteromeric amino acid transporters. For example, system b0,+ is a heterotetramer (b0,+AT-rBAT)2 as is system xC- (xCT-rBAT)2 although xCT-4F2hc does not effectively oligomerize (Fernandez et al., 2006). Nevertheless, a single heterodimer is the functional unit in all cases.



This family belongs to the .

 

References:

Baumer, Y., S. McCurdy, M. Alcala, N. Mehta, B.H. Lee, M.H. Ginsberg, and W.A. Boisvert. (2017). CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 256: 105-114.

Colavita, I., E. Nigro, D. Sarnataro, O. Scudiero, V. Granata, A. Daniele, A. Zagari, A. Pessi, and F. Salvatore. (2015). Membrane protein 4F2/CD98 is a cell surface receptor involved in the internalization and trafficking of human β-Defensin 3 in epithelial cells. Chem Biol 22: 217-228.

Devés, R. and C.A.R. Boyd. (2000). Surface Antigen CD98(4F2): not a single membrane protein, but a family of proteins with multiple functions. J. Membrane Biol. 173: 165-177.

Estévez, R., M. Camps, A.M. Rojas, X. Testar, R. Devés, M.A. Hediger, A. Zorzano, and M. Palacín. (1998). The amino acid transport system y+L/4F2hc is a heteromultimeric complex. FASEB J. 12: 1319-1329.

Estrach S., Lee SA., Boulter E., Pisano S., Errante A., Tissot FS., Cailleteau L., Pons C., Ginsberg MH. and Feral CC. (2014). CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction. Cancer Res. 74(23):6878-89.

Fernández, E., M. Jiménez-Vidal, M. Calvo, A. Zorzano, F. Tebar, M. Palacín, and J. Chillarón. (2006). The structural and functional units of heteromeric amino acid transporters. The heavy subunit rBAT dictates oligomerization of the heteromeric amino acid transporters. J. Biol. Chem. 281: 26552-26561.

Keriel, A., E. Botella, S. Estrach, G. Bragagnolo, A.C. Vergunst, C.C. Feral, and D. O''Callaghan. (2015). Brucella Intracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain. J Infect Dis 211: 1769-1778.

Krautz-Peterson, G., S. Camargo, K. Huggel, F. Verrey, C.B. Shoemaker, and P.J. Skelly. (2007). Amino acid transport in schistosomes: Characterization of the permeaseheavy chain SPRM1hc. J. Biol. Chem. 282: 21767-21775.

Malandro, M.S and M.S. Kilberg. (1996). Molecular biology of mammalian amino acid transporters. Annu. Rev. Biochem. 65: 305-336.

Markovich, D., G. Stange, J. Bertran, M. Palacin, A. Werner, J. Biber, and H. Murer. (1993). Two mRNA transcripts (rBAT-1 and rBAT-2) are involved in system b0,+-related amino acid transport. J. Biol. Chem. 268: 1362-1367.

Mastroberardino, L., B. Spindler, R. Pfeiffer, P.J. Skelly, J. Loffing, C.B. Shoemaker, and F. Verrey. (1998). Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395: 288-291.

Nguyen, N.N.T., Y.S. Lim, L.P. Nguyen, S.C. Tran, T.T.D. Luong, T.T.T. Nguyen, H.T. Pham, H.N. Mai, J.W. Choi, S.S. Han, and S.B. Hwang. (2018). Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation. Sci Rep 8: 15486.

Ohno, H., Y. Nakatsu, H. Sakoda, A. Kushiyama, H. Ono, M. Fujishiro, Y. Otani, H. Okubo, M. Yoneda, T. Fukushima, Y. Tsuchiya, H. Kamata, F. Nishimura, H. Kurihara, H. Katagiri, Y. Oka, and T. Asano. (2011). 4F2hc stabilizes GLUT1 protein and increases glucose transport activity. Am. J. Physiol. Cell Physiol. 300: C1047-1054.

Palacín, M., R. Estévez, J. Bertran, and A. Zorzano. (1998). Molecular biology of mammalian plasma membrane amino acid transporters. Physiol. Rev. 78: 969-1054.

Reynolds, B., P. Roversi, R. Laynes, S. Kazi, C.A. Boyd, and D.C. Goberdhan. (2009). Drosophila expresses a CD98 transporter with an evolutionarily conserved structure and amino acid-transport properties. Biochem. J. 420: 363-372.

Sato, H., A. Shiiya, M. Kimata, K. Maebara, M. Tamba, Y. Sakakura, N. Makino, F. Sugiyama, K. Yagami, T. Moriguchi, S. Takahashi, and S. Bannai. (2005). Redox imbalance in cystine/glutamate transporter-deficient mice. J. Biol. Chem. 280: 37423-37429.

Torrents, D., R. Estévez, M. Pineda, E. Fernández, J. Lloberas, Y.-B. Shi, A. Zorzano, and M. Palacín. (1998). Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L: a candidate gene for lysinuric protein intolerance. J. Biol. Chem. 273: 32437-32445.

Uemura, T., H.F. Yerushalmi, G. Tsaprailis, D.E. Stringer, K.E. Pastorian, L. Hawel, 3rd, C.V. Byus, and E.W. Gerner. (2008). Identification and characterization of a diamine exporter in colon epithelial cells. J. Biol. Chem. 283: 26428-26435.

Yan, Y., S. Vasudevan, H.T. Nguyen, and D. Merlin. (2008). Intestinal epithelial CD98: an oligomeric and multifunctional protein. Biochim. Biophys. Acta. 1780: 1087-1092.

Examples:

TC#NameOrganismal TypeExample
8.A.9.1.1rBAT Mammals rBAT of Oryctolagus cuniculus
 
8.A.9.1.2Neutral and basic amino acid transport protein rBAT (NBAT) (B(0,+)-type amino acid transport protein) (D2h)AnimalsSLC3A1 of Homo sapiens
 
Examples:

TC#NameOrganismal TypeExample
8.A.9.2.1

4F2hc of 527 aas and 1 TMS.  The 4F2/CDC98 cell surface receptor is involved in internalization of beta-defensin 3 (Colavita et al. 2015).

Mammals

4F2hc of Rattus norvegicus

 
8.A.9.2.2

The Slc3A2 (CD98hc; 4F2hc) accessory protein facilitates transport of amino acids and polyamines (putrescine/spermidine) (Uemura et al. 2008). 4F2hc stabilizes GLUT1 (2.A.1.1.28) and increase glucose transport activity (Ohno et al., 2011).  It forms a heterodimer with glycoprotein CD98 (LAT1; SLC7A5).  Contributes to tumorigenesis (Estrach et al. 2014).  CD98hc also modulates integrin signaling, plays a role in cell-to-cell fusion, and is essential for Brucella infection (Keriel et al. 2015). Hepatitis C virus (HCV) exploits SLC3A2 for viral propagation, and upregulation of SLC3A2 may contribute to HCV-mediated pathogenesis (Nguyen et al. 2018).

Animals

SLC3A2 of Homo sapiens

 
8.A.9.2.3

CD98hc, heavy chain of the heterodimeric CD998 (CG2791) amino acid transporter; involved in cell fusion, cell adhesion, TOR signalling, and amino acid transprot via LAT1 and LAT2 (see TC# 2.A.3.8.32) (Reynolds et al. 2009). CD98hc combines with one of six CD98lc proteins to regulate vascular smooth muscle cell proliferation in atherosclerosis (Baumer et al. 2017).

Animals

CD98hc of Drosophila melanogaster (Fruit fly)

 
Examples:

TC#NameOrganismal TypeExample
8.A.9.3.1SPRM1hc (Krautz-Peterson et al., 2007)WormsSPRM1hc of Schistosoma japonicum (Q5DDT5)