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  • The quaternary structure of many of the family B members

    2020-01-20

    The quaternary structure of many of the family B members (i.e., secretin, glucagon, glucagon-like peptide and ITD 1 receptors) have been actively studied and it has been demonstrated that they can form homodimers/oligomers (Gao et al., 2009; Ng & Chow, 2015; Ng, Lee, & Chow, 2013). Harikumar, Pinon, and Miller (2007) reported the existence of ligand-independent secretin receptor homodimerization; moreover, the same authors indicated that secretin and glucagon-like peptide-1 receptors form homodimeric complexes in which both protomers are associated along the lipid face of TM4 (Harikumar, Lau, Sexton, Wootten, & Miller, 2017). Very recently, Ward, Pediani, Harikumar, Miller, and Milligan (2017), using spatial intensity distribution analysis, demonstrated the existence of equilibrium between secretin receptor monomers and homodimers in CHO cells membrane, with little evidence of higher-order complexes, suggesting that there is likely a stable rate of association and dissociation of these complexes. In the same study, mutation of key residues in TM4 altered this equilibrium to greatly favor the monomeric state. Family B GPCRs also provide examples of receptors which are fully functional in their monomeric form such as the parathyroid hormone receptor and the glucagon-like peptide-1 receptors (Cai, Liu, et al., 2017; Pioszak, Harikumar, Parker, Miller, & Xu, 2010). In general, the ongoing development and improvement of membrane protein crystallography allowed resolving several crystal structures of GPCRs (Ghosh, Kumari, Jaiman, & Shukla, 2015). Several dimer interfaces have been found for class A receptors. One of the most frequent dimer interfaces involves symmetrical regions of TM1 and TM2 and H8 (rhodopsin, opsin, μ and k opioid and β1-adrenergic receptors). Other dimeric interfaces found are TM1–TM1, TM1–H8 (β1- and β2-adrenergic and dopamine D2 receptors) and TM4–TM5 or TM5–TM6 (rhodopsin, opsin, adenosine A2A, CXCR4, β1 and β2 receptors) (Baltoumas et al., 2016; Gonzalez et al., 2014). These GPCR dimer interfaces are similar to those predicted by mutagenesis, cross-linking and computational modeling (Provasi, Boz, Johnston, & Filizola, 2015), suggesting that they may have physiological relevance. Moreover, Baltoumas et al. (2016), using molecular dynamics and interface analysis, suggested the presence of conserved structural features in TM1–TM2–TM8, TM4–TM5 and TM5–TM6 of different GPCR dimers, despite the low sequence similarity usually found between the receptors. By using BiFC, proximity ligation assay (PLA) and radioligand binding techniques in the absence or presence of TM peptides that mimic specific TM domains of the receptors, disturbing the dimer interface, it has been reported the involvement of TM6–TM6 in D2R homodimers (Navarro et al., 2018; Pulido et al., 2018), TM6–TM6 in A2AR homodimers if D2Rs are present in the complex (Navarro et al., 2018) or TM4–TM5 in A2AR homodimers in the presence of A1Rs (Navarro et al., 2016).
    GPCRs form heteromers GPCRs are not only present as monomers and homomers but also form heteromers with other GPCRs (Ferré et al., 2014; Smith & Milligan, 2010). GPCR heteromers are macromolecular complexes, composed of at least two receptor units (protomers), with biochemical properties that are demonstrably different from those of their individual components (Ferré et al., 2009, Ferré et al., 2014; Gomes, Ayoub, et al., 2016). Three consensus criteria were published by the International Union of Basic and Clinical Pharmacology to facilitate the classification of true GPCR heteromers (Kenakin et al., 2010). The first of these criteria indicates that heteromer components not only must co-localize in the same subcellular compartment but also physically interact in native tissues (Albizu et al., 2010; Gomes, Ayoub, et al., 2016; Hounsou et al., 2015). The second consensus criteria requires that the heteromers must exhibit specific properties, which have to differ from those associated with the individual protomers, such as trafficking, ligand binding and signaling (biochemical fingerprint) (Bellot et al., 2015; Gomes, Ayoub, et al., 2016; Gomes, Ijzerman, Ye, Maillet, & Devi, 2011; González et al., 2012; Hillion et al., 2002; Jonas et al., 2018; Jordan & Devi, 1999; Kern, Albarran-Zeckler, Walsh, & Smith, 2012; Sohy, Parmentier, & Springael, 2007; Terrillon, Barberis, & Bouvier, 2004). Finally, criterion 3 postulates that heteromer disruption must lead to a loss of interaction and, consequently, a loss of its unique biochemical fingerprint (Baba et al., 2013; Fujita, Gomes, & Devi, 2015; Gomes, Ayoub, et al., 2016).