TMPRSS2 and ADAM17 interactions with ACE2 complexed with SARS-CoV-2 and B⁰AT1 putatively in intestine, cardiomyocytes, and kidney

COVID-19 outcomes reflect organ-specific interplay of SARS-CoV-2 and its receptor, ACE2, with TMPRSS2 and ADAM17. Confirmed active tropism of SARS-CoV-2 in epithelial cells of intestine and kidney proximal tubule, and in aging cardiomyocytes, capriciously manifests extra-pulmonary organ-related clinical symptoms in about half of COVID-19 patients, occurring by poorly understood mechanisms. We approached this knowledge gap by recognizing a clue that these three particular cell types share a common denominator kindred of uniquely expressing the SLC6A19 neutral amino acid transporter B⁰AT1 protein (alternatively called NBB, B, B⁰) serving glutamine and tryptophan uptake. B⁰AT1 is a cellular trafficking chaperone partner of ACE2, shown by cryo-EM to form a thermodynamically-favored stabilized 2ACE2:2B⁰AT1 dimer-of-heterodimers. The gut is the body’s site of greatest magnitude expression depot of both ACE2 and B⁰AT1. This starkly contrasts with pulmonary pneumocyte expression of monomeric ACE2 with conspicuously undetectable B⁰AT1. We hypothesized that B⁰AT1 steers the organ-related interplay amongst ACE2, TMPRSS2, ADAM17, and SARS-CoV-2 RBD. The present study employed molecular docking modeling that indicated active site catalytic pocket residues of TMPRSS2 and ADAM17 each formed bonds ≤ 2 A with monomer ACE2 specific residues within a span R652-D713 involved in cleaving sACE2 soluble ectodomain release. These bonds are consistent with competitive binding interactions of experimental anti-SARS-CoV-2 drug small molecules including Camostat and Nafamostat. Without B⁰AT1, ACE2 residues K657 and N699 dominated docking bonding with TMPRSS2 or ADAM17 active sites, with ACE2 R710 and R709 contributing electrostatic attractions, but notably ACE2 S708 never closer than 16-44 A. However, in the dimer-of-heterodimers arrangement all ACE2 neck region residues were limited to TMPRSS2 or ADAM17 approaches 35 A, with the interference directly attributed to the presence of a neighboring B⁰AT1 subunit complexed to the partnering ACE2 subunit of 2ACE2:2B⁰AT1; ADAM17 failed to dock by bumping its active site pocket oriented dysfunctionally outwardly facing 180⁰away. Results were the same whether the dimer-of-heterodimers was in either the “closed” or “open” conformation, or whether or not SARS-CoV-2 RBD was complexed to ACE2. The results implicate B⁰AT1-and in particular the 2ACE2:2B⁰AT1 complex-as a maJor player in the landscape of COVID-19 pathophysiology engaging TMPRSS2 and ADAM17, consistent with experimental evidence in the literature and in clinical reports. These findings provide a gateway to understanding the roles of B⁰AT1 relating to COVID-19 manifestations putatively assigned to intestinal and renal epithelial cells and cardiomyocytes, with underpinnings useful for considerations in public hygiene policy and drug development.