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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). 

Viral entry into the host cell is the first step towards successful infection. Viral entry starts with virion attachment, and binding to receptors. Receptor binding viruses either directly release their genomes into the cell, or enter cells through endocytosis. For DNA viruses and a few RNA viruses, the endocytosed viruses is transported from cytoplasm into the nucleus followed by gene expression. The receptor for infection by white spot syndrome virus (WSSV) for kuruma shrimp, Marsupenaeus japonicus, is a member of the immunoglobulin superfamily (IgSF) with a transmembrane region, and is similar to the vertebrate polymeric immunoglobulin receptor (pIgR). MjpIgR was detected in all tissues tested, and its expression was induced by WSSV infection. Knockdown of MjpIgR, and blocking MjpIgR with its antibody inhibited WSSV infection, and overexpression facilitated the invasion. The extracellular domain of MjpIgR interacts with envelope protein VP24 of WSSV and the intracellular domain interacts with calmodulin (MjCaM). MjpIgR oligomerizes and is internalized by clathrin-dependent endocytosis (Niu et al. 2019).

CD4 is an integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses to both external and internal stimuli. In T-cells,  it functions primarily as a coreceptor for MHC class II molecule:peptide complex (Doyle and Strominger 2006). The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. CD4 interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen-presenting cells (APCs) (Bernstein et al. 2006). In turn, it recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates, ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, it plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway (Zhen et al. 2014) while participating in the development of T-helper cells in the thymus and triggering the differentiation of monocytes into functional mature macrophages (Zhen et al. 2014).  It is the primary receptor for human immunodeficiency virus-1 (HIV-1) (Crise et al. 1990, Sharma et al. 2005, Matthias et al. 2002). It is down-regulated by HIV-1 Vpu (Lindwasser et al. 2007) and acts as a receptor for human Herpes virus 7/HHV-7 (Lusso et al. 1994). CD4 and its co-receptor, CCR5, exist in the membrane in a fluid state that may be essential for membrane fusion between the viral envelop and the cell membrane (Matthias et al. 2002).

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