Figure 2
Localizations of AA variations to secondary structures and interfaces of nAChR hα6 subunit. [(A) and (B)] AA residues undergoing variation are identified in a 3D model of the nAChR hα6 subunit: A 3D homology model of the nAChR hα6 subunit was generated based on the crystal structure of Torped o muscle nAChR α subunit (PDB code: 2BG9:A). Hence structural features are approximate and may deviate from what seen with α subunit of Torped o muscle nAChR. β strands constitute inner β-sheet (strand β1-β3, β5, β6 and β8) and outer β-sheet (strand β4, β7, β9 and β10); and are connect to each other via loops. These loops constitute positive (+) (loops A, B and C) and negative face (loops D, E and F) of α6 subunit and contribute to subunit assembly, ligand binding, and formation of ligand binding pocket and/or coupling agonist binding to channel gating. Cysteine loop and other loop residues undergone variations are also identified. [(C)-(E)] Interfaces contributed by α6 subunit to formation of α6*-nAChR: Adhering to the canonical rule of pentamer formation, α6β2-nAChR would be formed out of three α6 and two β2 subunits [i.e., (i) (α6)3(β2)2-nAChR] or two α6 and three β2 subunits [i.e., (ii) (α6)2(β2)3-nAChR]. In the event β3 or gain-of-function β3 (i.e., β3V9’S) subunits to be integrated into α6β2*-nAChR complexes these subunits would take the position of 3rd α6 subunit in the 1st (i) configuration or 3rd β2 subunit in the 2nd (ii) configuration [i.e., (iii) (α6)2(β2)2(β3or β3V9’S)-nAChR]. Similarly, β4 subunit would substitute β2 subunit for formation human α6β4-[i.e., (α6)3(β4)2 and (α6)2(β4)3]-nAChR. For formation of (α6)2(β4)2β3- or (α6)2(β4)2β3V9’S-nAChR β3 or β3V9’S subunits would substitute one α6 subunit in (α6)3(β4)2 configuration or one β4 subunit in (α6)2(β4)3 configuration. Two presumed agonist (ACh or nicotine and others) binding sites in the interface of α6(+) and β2(−) subunits are identified as ovals. Variations in the structural loops in the (−)-ve face (loop D, E and F) and (+)-ve face (loop A, B and C) of the hα6 subunit are expected to affect the function of hα6*-nAChRs involving interfaces identified by arrow marks.