ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S protein priming by host cell serine protease TMPRSS2. Recently COVID19 has been declared pandemic by World Health Organization yet high differences in disease outcomes across countries have been seen. We provide evidences based on analyses of existing public datasets and by using various insilico approaches to explain some of these as factors that may explain population level differences. One of the key factors might be entry of virus in host cells due to differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that higher expression of ACE2 facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs) and with different frequencies in different populations, results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2 and becomes more difficult in presence of broad neutral amino acid transporter, B0AT1 (coded by SLC6A19), that usually does not express in Lungs. We also propose that the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of Virus in host cells. In addition, we suggest some other potential key host genes like ADAM17, RPS6, HNRNPA1, SUMO1, NACA,

Ethnicity-dependent allele frequencies are correlated with COVID-19 case fatality rate

“…In line with previous reports, we suggest that V197M acts to indirectly compromise the binding a nity of TMPRSS2 to SARS-CoV-2 spike protein and ACE2 [35][36][37] . This implies a protective role of the V197M variant against SARS-CoV-2 infections, but neither we nor previous researchers [36][37][38] have uncovered any clear evidence or explanation for causation. Interestingly, the change from valine to methionine has a Grantham distance matrix value of only 22, the shortest distance from valine to any amino acid.…”

Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

“…For a list of candidate genes proposed by previous study on the molecular virology of SARS-CoV-2, we identified that the missense variant rs12329760 in TMPRSS2 was less frequent among the critical patients compared to the rest of the patients and the general population. This variant results in an alteration of the valine to the methionine at the 197th amino acids (p.Val197Met) that has been predicted to decrease the TMPRSS2 protein stability and ACE2 binding 44 . On the other hand, our study using Chinese samples did not support the assumption 29 that host genetic factors in the essential SARS-CoV receptor ACE2 and some other genes involved in the host-pathogen interaction network might play a role in determining the patient's severity or susceptibility.…”

“…Particularly, we have inspected the missense and loss of function variants present in the SARS-CoV-2 S protein host cellular receptor gene ACE2 and the S protein primer gene TMPRSS2 that were known to have played a critical role in controlling the viral entry into the host cell, as well as a few other genes that were predicted to play a role in the host-pathogen interaction network like SLC6A19, ADAM17, RPS6, HNRNPA1, SUMO1, NACA, and BTF3 44 . The majority of the functional variants have minor allele frequency (MAF) less than 1% except for the p.Val197Met missense variant in TMPRSS2 (Fig.…”

“…S12). Computational protein modeling suggested that the p.Val197Met TMPRSS2 isoform decrease the stability of the TMPRSS2 protein, promote the binding to S-protein and inhibit its binding with ACE2 44 . The decreasing allele frequency in the severe patient groups supports that the p.Val197Met is related to the disease outcomes of COVID-19.…”

ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

“…[49] Specific studies on ACE2 dynamics and allostery have not been performed, although molecular dynamics simulations are presently being carried out. [50][51] In the absence of specifically designed experimental studies, we can deduce dynamics and allostery from biochemical, chemical biology and structural work published over the years.…”