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).
Extracellular chaperone protein precursor, Basigin (BSG; CD147). Interacts with MCT1, 3 and 4 (TC# 2.A.1.13.1, 7 and 9, respectively) (Ovens et al., 2010; Halestrap 2012). May play a role in cancer progression (Kendrick et al. 2016).
Basigin precursor of Homo sapiens (P35613)
Activated leukocyte cell adhesion molecule, ALCAM or CD166 antigen, of 583 aas and 2 TMSs, N- and C-terminal. It is expressed on and in the cell membranes of various cells. In the spinal cord dorsal horn (DH), the first gate for the sensory and pain transmission to the brain, ALCAM plays modulatory roles in the excitatory synaptic transmission and plasticity in the (rat) spinal DH (Park et al. 2017).
ALCAM of Homo sapiens
Interleukin 1 receptor of 569 aas and 2 TMSs, N-terminal and near the middle of the protein. It is the receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1, it associates with the coreceptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. It binds ligands with comparable affinity, and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex (Slack et al. 2000).
IL-1R of Homo sapiens
cSrc tyr kinase of 536 aas; regulates the Na+,K+-ATPase and connexin 43, probably by direct phosphorylation (Giepmans 2006).
cSrc of Homo sapiens
Epidermal growth factor receptor (EGFR) of 1426 aas and 2 or more TMSs. Binds to four ligands: Spitz, Gurken, Vein and Argos, transducing signals through the ras-raf-MAPK pathway. Involved in a myriad of developmental decisions (Geiger et al. 2011).
EGFR of Drosophila melanogaster (Fruit fly)
Coxsackievirus and adenovirus receptor, CAR, of 365 aas and 2 TMSs, a component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. It is also involved in transepithelial migration of leukocytes through adhesive interactions with JAML, a transmembrane protein of the plasma membrane of leukocytes (Cohen et al. 2001). It's subcellular distribution has been studied (Ifie et al. 2018).
CAR of Homo sapiens
Ephrin type-B receptor 4 (EPHB4; EC:188.8.131.52). Alternative name(s): Hepatoma transmembrane kinase; Tyrosine-protein kinase, TYRO11. It is a receptor tyrosine kinase which binds
promiscuously transmembrane ephrin-B family ligands residing on adjacent
cells, leading to contact-dependent bidirectional signaling into
neighboring cells. It plays a role in postnatal blood vessel remodeling, morphogenesis and permeability (Erber et al. 2006; Martin-Almedina et al. 2016).
EPHB4 of Homo sapiens
Angiopoietin-1 receptor of 1072 aas, Tek, a tyrosyl protein kinase (Ward and Dumont 2002).
Tek of Mus musculus
Receptor tyrosyl protein kinase, ErbB4 (ErbB-4). Plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis (Deng et al. 2013).
ErbB4 of Homo sapiens
Tex14 of 1497 aas and 1 or 2 TMSs. Required both for the formation of
intercellular bridges during meiosis and for kinetochore-microtubule
attachment during mitosis. Intercellular bridges, called 'ring canals', probably result from nurse cell fusion with the developing oocyte. They are evolutionarily
conserved structures that connect differentiating germ cells and are
required for spermatogenesis, oogenesis and male fertility. They act by promoting the
conversion of midbodies into intercellular bridges via its interaction
with CEP55. Interaction with CEP55 inhibits the interaction between
CEP55 and PDCD6IP/ALIX and TSG101, blocking cell abscission and leading
to transformation of midbodies into intercellular bridges. In spite of its PK domain, it has no protein kinase activity in vitro (Lei and Spradling 2016).
Tex14 of Homo sapiens
The Advanced glycosylation end product-specific receptor of 404 aas and 2 TMSs, N- and C-terminal, AGER or RAGE. It is the receptor for amyloid beta peptide, and it contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. RAGE also has a number of other functions (Fang et al. 2010;.Jin et al. 2011). It's structure is known to 1.5 Å resolution (Park et al. 2010; Xue et al. 2011).
RAGE of Homo sapiens
Extracellular chaperone protein precursor, Embigin. Interacts with MCT2 (2.A.1.13.5) (Ovens et al., 2010; Halestrap 2012).
Embigin of Homo sapiens (Q6PCB8)
Polymeric immunoglobulin receptor-like protein, pIgR, of 562 aas and 2 TMSs, one N-terminal and one near the C-terminus of the protein. It is the receptor for white spot syndrome virus (WSSV) infection (Niu et al. 2019).
pIgR of Penaeus japonicus (Kuruma prawn) (Marsupenaeus japonicus)
Polymeric Ig-like receptor of 345 aas and 2 TMSs, pIgR, also called Cell adhesion molecule 4 isoform X2.
pIgR of Homo sapiens
Polymeric Ig-like receptor family protein, pIgR, of 774 aas and 1 TMS, near the C-terminus.
pIgR of Drosophila melanogaster (Fruit fly)
Poliovirus receptor-related protein 3-like isoform X, PVRL3, of 366 aas and 1 N-terminal TMS
PVRL3 of Lipotes vexillifer (Yangtze river dolphin)
Uncharacterized protein of 323 aas and 2 TMSs, N- and C-terminal.
UP of Strongylocentrotus purpuratus
T-cell surface antigen CD2 of 351 aas. CD2 interacts with lymphocyte function-associated antigen CD58 (LFA-3) and CD48/BCM1 to mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, and the cytoplasmic domain is implicated in the signaling function.
CD2 of Homo sapiens
Carcinoembryonic antigen-related cell adhesion molecule 1-like protein of 663 aas and 1 TMS. This protein appears to be related to members of family 8.A.128, and these two families may comprise a superfamily.
Adhesin of Xenopus laevis
TGF-β (Tkv) receptor protein kinase of 575 aas and 1 TMS (Bartoszewski et al. 2004).
Tkv receptor of Drosophila melanogaster (Fruit fly)
Neural cell adhesion molecule 2-like protein of 567 aas and 2 TMSs, N- and C-terminal.
Adhesion protein of Astatotilapia calliptera (eastern happy)
Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (Tan-Sindhunata et al. 2015). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex (Koppel et al. 2019).
MUSK of Homo sapiens
Potassium channel associated protein, contactin 2 (CNTN2). Mutations are associated with autosomal recessive cortical myoclonic tremors and epilepsy (Stogmann et al. 2013).
CNTN2 of Homo sapiens
Insulin receptor-like tyrosine kinase, DAF2, of 1846 aas and 3 putative TMSs, one near the N-terminus, and two in the C-terminal part ofthe protein. It regulates metabolism, controls longevity and prevents developmental arrest at the dauer stage (Fierro-González et al. 2011; Tiku et al. 2017; Chen et al. 2013). The nematode insulin receptor (IR), DAF-2B, modulates insulin signaling by sequestration of insulin peptides (Martinez et al. 2020).
DAF2 of Caenorhabditis elegans
Hemicentin-1-like protein of 321 aas and 0 - 4 TMSs.
Him1 of Penaeus vannamei
Hepatocyte cell adhesion molecule (CAM) precursor of 416 aas. Important for interactions, trafficking and function of ClC2 (CLC-2) in several tissues including the nervious system where it influences human leukodystrophies (Capdevila-Nortes et al. 2015).
CAM of Homo sapiens
Fibroblast growth factor receptor-like protein, FGFRL1, of 504 aas and 2 TMSs, one N-terminal and one C-terminal. It is capable of inducing syncytium formation (Steinberg et al. 2010).
FGFRL-1 of Homo sapiens
Fibroblast growth factor receptor 1, FGFR1, of822 aas and 2 TMSs, one N-terminal and one central. FGFR1 is a tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system (Haenzi and Moon 2017).
FGFR1 of Homo sapiens
Neuroplastin NptN of 398 aas (Beesley et al. 2014). Important for targetting of certain transporters such as Xkr8 to the plasma membrane with which it, with basigin, forms a physical complex (Suzuki et al. 2016).
NptN of Homo sapiens
Fibroblast growth factor receptor 4, FGFR4, of 802 aas and 2 - 4 TMSs. Serves as the receptor for FGF23 for the activation of TRP6 (TC# 1.A.4.1.5). Binding activates the TRP6 channel for inorganic cation (including Ca2+) transport (Smith et al. 2017). It also regulates Na+:phosphate co-transport together with α-Klotho (see paragraph 2 in the family description of TC# 1.A.108; Hu et al. 2018).
FGFR4 of Homo sapiens
T-cell surface glycoprotein, CD4, of 458 aas and 2 TMSs, N- and C-terminal. It is the receptor for HIV and other viruses (see family description) (Raphael et al. 2020).
CD4 of Homo sapiens
CD4-like protein 2 of 429 aas and 2 TMSs, N- and C-terminal.
CD4 of Ctenopharyngodon idella (grass carp)
Lymphocyte activation gene 3 protein of 487 aas and 2 TM
Lymphocyte activation protein of Thamnophis elegans (Western garter snake)
Neural cell adhesion molecule 2-like protein of 496 aas and 2 TMSs, N- and C-terminal.
Cell adhestion protein of Tachysurus fulvidraco (yellow cat fish)
Uncharacterized protein of 414 aas and 2 TMSs, N- and C-terminal.
UP of Colinus virginianus (northern bobwhite)
TMEM25 protein of 279 aas and 1 TMS.
TMEM25 of Neopelma chrysocephalum (saffron-crested tyrant-manakin)
TMEM25 of 366 aas and up to 4 TMSs, scattered throughout the protein. The expression of the Tmem25 is strongly influenced by glutamate ionotropic receptor kainate type subunit 4, and it is primarily localized to late endosomes in neurons (Zhang et al. 2019). The effects of TMEM25 on neuronal excitability are likely mediated by N-methyl-D-aspartate receptors. TMEM25 affects the expression of the NR2B subunit and interacts with NR2B; both colocalize to late endosome compartments. TMEM25 induces acidification changes in lysosome compartments and accelerates the degradation of NR2B, and TMEM25 expression is decreased in brain tissues from patients with epilepsy and epileptic mice. TMEM25 overexpression attenuated the behavioral phenotypes of epileptic seizures, whereas TMEM25 downregulation exerted the opposite effect (Zhang et al. 2019).
TMEM25 of Homo sapiens
TMEM25-like protein, isoform X3 of 169 aas and 1 TMS.
TMEM25 of Pteropus alecto