Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders

Cholinergic alpha 7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dup alpha 7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the alpha 7 receptor have been replaced by 27 residues from FAM7. Dup alpha 7 negatively affects the functioning of alpha 7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the alpha 7 nicotinic receptor containing dup alpha 7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type alpha 7 and dup alpha 7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dup alpha 7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dup alpha 7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dup alpha 7/alpha 7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dup alpha 7/dup alpha 7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, alpha-bungarotoxin, and amyloid A beta(42). Our findings show that the optimal stoichiometry of dup alpha 7/alpha 7 functional pentamers should be no more than three dup alpha 7 monomers, in favour of a dup alpha 7/alpha 7 interface in comparison to a homodimer dup alpha 7/dup alpha 7 interface. We also showed that receptors bearing dup alpha 7 subunits are less sensitive to A beta(42) effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.

Automated summary

This study investigated the impact of dup alpha 7 on alpha 7 receptors through computational models and molecular dynamics simulations, revealing that receptors with four or more dup alpha 7 subunits are unstable while models with dup alpha 7/alpha 7 interfaces are more stable. The optimal stoichiometry is no more than three dup alpha 7 monomers in favor of dup alpha 7/alpha 7 interface.