A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection relies on the binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells. Regions of the S protein have been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. α7 nAChR is an interesting candidate target since it is present in neuronal and non-neuronal cells, including immune cells, and has anti-inflammatory actions. We here identified a novel direct functional interaction between the α7 nAChR and a region of the S protein (Y674-R685). The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive inhibitor. It activates the α7 nAChR, in line with our previous molecular dynamics simulations showing favorable binding of this accessible region of the S protein to the nAChR agonist binding pocket. However, activation requires the presence of positive allosteric modulators that enhance channel opening probability, indicating very low activation efficacy. The S fragment exerts an additional inhibition, which may be the predominant effect on α7 responses. This study reveals a functional interaction between α7 and the Y674-R685 fragment of the S protein, which opens doors for exploring the involvement of nAChRs in COVID-19 pathophysiology.

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“…The spike glycoprotein, which is located on the surface of the virion, mediates SARS-CoV-2 entry into host cells by binding primarily to the receptor angiotensin-converting enzyme 2 (ACE2) ( 1, 2 ) as well as to other receptors, such as neuropilin-1 ( 3, 4 ) and potentially nicotinic acetylcholine receptors ( 5, 6 ). The spike ectodomain (Figure 1A and Figure S2) contains the domain that directly binds to the human receptors (named receptor-binding domain, RBD) as well as all the machinery needed to fuse the host and viral membranes, including the fusion peptide (FP) ( 7–9 ).…”