TMPRSS2 and ADAM17 interactions with ACE2 complexed with SARS-CoV-2 and B 0 AT1 putatively in intestine, cardiomyocytes, and kidney
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Abstract
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 B 0 AT1 protein (alternatively called NBB, B, B 0 ) serving glutamine and tryptophan uptake. B 0 AT1 is a cellular trafficking chaperone partner of ACE2, shown by cryo-EM to form a thermodynamically-favored stabilized 2ACE2:2B 0 AT1 dimer-of-heterodimers. The gut is the body’s site of greatest magnitude expression depot of both ACE2 and B 0 AT1. This starkly contrasts with pulmonary pneumocyte expression of monomeric ACE2 with conspicuously undetectable B 0 AT1. We hypothesized that B 0 AT1 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 B 0 AT1, 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 B 0 AT1 subunit complexed to the partnering ACE2 subunit of 2ACE2:2B 0 AT1; ADAM17 failed to dock by bumping its active site pocket oriented dysfunctionally outwardly facing 180 0 away. 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 B 0 AT1-and in particular the 2ACE2:2B 0 AT1 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 B 0 AT1 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.
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SciScore for 10.1101/2020.10.31.363473: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Protein-protein interaction software ClusPro 2.0 [57-59] was employed for molecular docking simulations which involved 70,000 rotations probing rigid body docking, clustering of lowest energy complexes, and final energy minimization. ClusProsuggested: (ClusPro, RRID:SCR_018248)For each paired docking of ligand chain with receptor chain, the Cluster 0 set of residues garnering the greatest clustering and most negative docking energy score was assessed for interface contact distances using ChimeraX software [61] meeting default probe criteria 1.4 A or being buried with a 15 A2 area cutoff; … SciScore for 10.1101/2020.10.31.363473: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Protein-protein interaction software ClusPro 2.0 [57-59] was employed for molecular docking simulations which involved 70,000 rotations probing rigid body docking, clustering of lowest energy complexes, and final energy minimization. ClusProsuggested: (ClusPro, RRID:SCR_018248)For each paired docking of ligand chain with receptor chain, the Cluster 0 set of residues garnering the greatest clustering and most negative docking energy score was assessed for interface contact distances using ChimeraX software [61] meeting default probe criteria 1.4 A or being buried with a 15 A2 area cutoff; such interface contact distances were typically ≤ 2.0 A. ChimeraXsuggested: (UCSF ChimeraX, RRID:SCR_015872)Monomers, homodimers, heterodimers, and tetramers were derived by parsing chains of 6M17, 6M18, or 6M1D using PDBEditor [62] and PyMOL v2.4.0 [60]. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Repository (UniProtKB accession O15393) human isoform-2 [49-51, 64] built on the PBD ID: 5CE1.1. UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)Ramachandran plot validation of the overall structure and placement of active site residues was conducted using MolProbity ver. MolProbitysuggested: (MolProbity, RRID:SCR_014226)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 7. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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