Amino acid transporter B ⁰ AT1 influence on ADAM17 interactions with SARS-CoV-2 receptor ACE2 putatively expressed in intestine, kidney, and cardiomyocytes

SARS-CoV-2 exhibits significant experimental and clinical gastrointestinal, renal, and cardiac muscle tropisms responsible for local tissue-specific and systemic pathophysiology capriciously occurring in about half of COVID-19 patients. The underlying COVID-19 mechanisms engaged by these extra-pulmonary organ systems are largely unknown. We approached this knowledge gap by recognizing that neutral amino acid transporter B ⁰ AT1 (alternately called NBB, B, B ⁰ in the literature) is a common denominator expressed nearly exclusively by three particular cell types: intestinal epithelia, renal proximal tubule epithelium, and cardiomyocytes. B ⁰ AT1 provides uptake of glutamine and tryptophan. The gut is the main depot expressing over 90% of the body’s entire pool of SARS-CoV-2 receptor angiotensin converting enzyme-2 (ACE2) and B ⁰ AT1. Recent cryo-EM studies established that ACE2 forms a thermodynamically favored dimer-of-heterodimers complex with B ⁰ AT1 assembled in the form of a dimer of two ACE2:B ⁰ AT1 heterodimers anchored in plasma membranes. Prior epithelial cell studies demonstrated ACE2 chaperone trafficking of B ⁰ AT1. This contrasts with monomeric expression of ACE2 in lung pneumocytes, in which B ⁰ AT1 is undetectable. The cell types in question also express a disintegrin and metalloproteinase-17 (ADAM17) known to cleave and shed the ectodomain of monomeric ACE2 from the cell surface, thereby relinquishing protection against unchecked renin-angiotensin-system (RAS) events of COVID-19. The present study employed molecular docking modeling to examine the interplaying assemblage of ACE2, ADAM17 and B ⁰ AT1. We report that in the monomer form of ACE2, neck region residues R652-N718 provide unimpeded access to ADAM17 active site pocket, but notably R708 and S709 remained >10-15 Å distant. In contrast, interference of ADAM17 docking to ACE2 in a dimer-of-heterodimers arrangement was directly correlated with the presence of a neighboring B ⁰ AT1 subunit complexed to the partnering ACE2 subunit of the 2ACE2:2B ⁰ AT1] dimer of heterodimers, representing the expression pattern putatively exclusive to intestinal, renal and cardiomyocyte cell types. The monomer and dimer-of-heterodimers docking models were not influenced by the presence of SARS-CoV-2 receptor binding domain (RBD) complexed to ACE2. The results collectively provide the underpinnings for understanding the role of B ⁰ AT1 involvement in COVID-19 and the role of ADAM17 steering ACE2 events in intestinal and renal epithelial cells and cardiomyocytes, with implications useful for consideration in pandemic public hygiene policy and drug development.