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8.A.23 The Basigin (Basigin) Family

Basigin precursor protein of man is also called CD147, 5F7, emmprin, leukocyte activation antigen, MP, (tumor-derived) collagenase stimulating factor, and extracellular matrix metalloproteinase inhibitor. It is a chaperone glycoprotein with an N-terminal leader peptide that is probably removed by proteolysis after secretion. It has a second TMS near its C-terminus. Additionally, it has two IGcan immunoglobulin-like cell adhesion domains (positions 20-110 and 220-310). The protein directs transporters such as MCT1, MCT2. MCT3 amd MCT4 but not MCT8 (2.A.1.13) to the plasma membrane and remains bound to them, being required for activity and for sensitivity to inhibition by organomercurials (Wilson et al., 2005; Halestrap 2013).  It appears to regulate complex I activity and apoptosis in mitochondria by interacting with mitochondrial NDUFS6 (Luo et al. 2014).  It has many homologues in vertebrate and invertebrate animals, and several of these have been functionaly characterized. The role of basigin in regulating many transporters has been reviewed (Muramatsu 2016).

Basigin is the receptor for cyclophilins, S100A9, and platelet GPVI, while basigin-1 serves as the receptor for the rod-derived cone viability factor (Muramatsu 2015). As noted above, basigin tightly associates with monocarboxylate transporters, and is essential for their cell surface translocation and activities, but  it also associates with other proteins including GLUT1, CD44, and CD98. The carbohydrate portion is recognized by lectins, such as galectin-3 and E-selectin. These molecular recognitions form the basis for the role of basigin in the transport of nutrients, migration of inflammatory leukocytes, and induction of matrix metalloproteinases. Basigin is important in vision, spermatogenesis, and other physiological phenomena, and plays roles in the pathogenesis of numerous diseases, including cancer. It is also the receptor for an invasive protein RH5, which is present in malaria parasites.

Contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, and another transmembrane protein called contactin associated protein-like 2 (CNTNAP2 alias CASPR2) are together necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. CNTN2 knockout mice were previously reported to suffer from spontaneous seizures and mutations in the CNTNAP2 gene have been described to cause myoclonic tremor and epilepsy in humans (Stogmann et al. 2013).

The rat liver C-BAT is a 110 kDa glycoprotein (GP110) of 519 amino acids. Its short C-terminus is in the cytoplasm, it spans the membrane once, and the majority of the protein is external. It contains the ATP-binding consensus site (residues 92-100) of GPAYSGRET and is an ecto-ATPase. Transfection of heterologous cells with the cDNA encoding this protein conferred both bile acid transport and ecto-ATPase activity to the recipient cells (Sippel et al. 1993; 1994). Taurocholate is pumped out of the cell. Transport (but not ATPase activity) appears to be stimulated by protein kinase C-mediated phosphorylation of the C-terminal domain. The ecto-ATPase activity of this protein does not appear to mediate transport although reduction in the cytoplasmic ATP concentration reduces the transport rate. Both ATP and the membrane potential have been implicated as energy sources for transport.

The topology of the rat liver C-BAT protein as a Type I membrane protein, the dissection of its transport activity from its ecto-ATPase activity, its homology to members of the carcinogenic antigen superfamily and its identification as a calcium-independent cell adhesin in the apical membrane of the hepatocyte all suggest that this protein does not alone function as a bile acid efflux pump (Suchy et al. 1997). The involvement of at least one other protein is suggested, and this other protein may be the primary bile acid export permease. GP110 may thus be an accessory protein, possibly an activator that is responsive to protein kinase (Halestrap 2013).

Neuroplastins are homologous to and function like basigins. Of these, both np65 and np55 induce neurite outgrowth, and both activate the FGF receptor and associated downstream signalling pathways. Np65 binds to and colocalises with GABA(A) receptor subtypes (TC # 1.A.9) and may play a role in anchoring them to specific synaptic and extrasynaptic sites. The neuroplastins have been shown to chaperone and support the monocarboxylate transporter MCT2 in transporting lactate across the neuronal plasma membrane. The neuroplastins are multifunctional adhesins that support neurite outgrowth, modulate long-term activity-dependent synaptic plasticity, regulate surface expression of GluR1 receptors, modulate GABA(A) receptor localisation, and play a key role in delivery of monocarboxylate energy substrates both to the synapse and to extrasynaptic sites (Beesley et al. 2014).

This family belongs to the: Protein Kinase (PK) Superfamily.

References associated with 8.A.23 family:

Beesley, P., M. Kraus, and N. Parolaro. (2014). The neuroplastins: multifunctional neuronal adhesion molecules--involvement in behaviour and disease. Adv Neurobiol 8: 61-89. 25300133
Capdevila-Nortes X., Jeworutzki E., Elorza-Vidal X., Barrallo-Gimeno A., Pusch M. and Estevez R. (2015). Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy. J Physiol. 593(18):4165-80. 26033718
Giepmans, B.N. (2006). Role of connexin43-interacting proteins at gap junctions. Adv Cardiol 42: 41-56. 16646583
Haenzi, B. and L.D. Moon. (2017). The Function of FGFR1 Signalling in the Spinal Cord: Therapeutic Approaches Using FGFR1 Ligands after Spinal Cord Injury. Neural Plast 2017: 2740768. 28197342
Halestrap, A.P. (2012). The monocarboxylate transporter family--Structure and functional characterization. IUBMB Life 64: 1-9. 22131303
Halestrap, A.P. (2013). The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med 34: 337-349. 23506875
Kendrick, A.A., J. Schafer, M. Dzieciatkowska, T. Nemkov, A.D. Alessandro, D. Neelakantan, H.L. Ford, C.G. Pearson, C.D. Weekes, K.C. Hansen, and E.Z. Eisenmesser. (2016). CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming. Oncotarget. [Epub: Ahead of Print] 28039486
Luo, Z., W. Zeng, W. Tang, T. Long, J. Zhang, X. Xie, Y. Kuang, M. Chen, J. Su, and X. Chen. (2014). CD147 interacts with NDUFS6 in regulating mitochondrial complex I activity and the mitochondrial apoptotic pathway in human malignant melanoma cells. Curr Mol Med 14: 1252-1264. 25470292
Muramatsu, T. (2016). Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem 159: 481-490. 26684586
Ovens, M.J., C. Manoharan, M.C. Wilson, C.M. Murray, and A.P. Halestrap. (2010). The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem. J. 431: 217-225. 20695846
Park, E.S., S.M. Jeon, H. Weon, H.J. Cho, and D.H. Youn. (2017). Activated leukocyte cell adhesion molecule is involved in excitatory synaptic transmission and plasticity in the rat spinal dorsal horn. Neurosci Lett 656: 9-14. 28720382
Sippel, C.J., F.J. Suchy, M. Ananthanarayanan, and D.H. Perlmutter. (1993). The rat liver ecto-ATPase is also a canalicular bile acid transport protein. J. Biol. Chem. 268: 2083-2091. 8420979
Sippel, C.J., M.J. McCollum, and D.H. Perlmutter. (1994). Bile acid transport by the rat liver canalicular bile acid transport/ecto-ATPase protein is dependent on ATP but not on its own ecto-ATPase activity. J. Biol. Chem. 269: 2820-2826. 8300615
Slack, J.L., K. Schooley, T.P. Bonnert, J.L. Mitcham, E.E. Qwarnstrom, J.E. Sims, and S.K. Dower. (2000). Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J. Biol. Chem. 275: 4670-4678. 10671496
Smith, E.R., S.G. Holt, and T.D. Hewitson. (2017). FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction. Int J Biochem. Cell Biol. 92: 63-78. 28919046
Steinberg, F., S.D. Gerber, T. Rieckmann, and B. Trueb. (2010). Rapid fusion and syncytium formation of heterologous cells upon expression of the FGFRL1 receptor. J. Biol. Chem. 285: 37704-37715. 20851884
Stogmann, E., E. Reinthaler, S. Eltawil, M.A. El Etribi, M. Hemeda, N. El Nahhas, A.M. Gaber, A. Fouad, S. Edris, A. Benet-Pages, S.H. Eck, E. Pataraia, D. Mei, A. Brice, S. Lesage, R. Guerrini, F. Zimprich, T.M. Strom, and A. Zimprich. (2013). Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2. Brain 136: 1155-1160. 23518707
Suchy, F.J., C.J. Sippel, and M. Ananthanarayanan. (1997). Bile acid transport across the hepatocyte canalicular membrane. FASEB J. 11: 199-205. 9068608
Suzuki, J., E. Imanishi, and S. Nagata. (2016). Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc. Natl. Acad. Sci. USA 113: 9509-9514. 27503893
Wilson, M.C., D. Meredith, J.E. Fox, C. Manoharan, A.J. Davies, and A.P. Halestrap. (2005). Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J. Biol. Chem. 280: 27213-27221. 15917240