Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2
COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10-15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2022
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| Online Access: | https://hdl.handle.net/10356/154952 |
| _version_ | 1811682292658077696 |
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| author | Suryamohan, Kushal Diwanji, Devan Stawiski, Eric W. Gupta, Ravi Miersch, Shane Liu, Jiang Chen, Chao Jiang, Ying-Ping Fellouse, Frederic A. Sathirapongsasuti, J. Fah Albers, Patrick K. Deepak, Tanneeru Saberianfar, Reza Ratan, Aakrosh Washburn, Gavin Mis, Monika Santhosh, Devi Somasekar, Sneha Hiranjith, G. H. Vargas, Derek Mohan, Sangeetha Phalke, Sameer Kuriakose, Boney Antony, Aju Ustav, Mart Schuster, Stephan Christoph Sidhu, Sachdev Junutula, Jagath R. Jura, Natalia Seshagiri, Somasekar |
| author2 | Singapore Centre for Environmental Life Sciences and Engineering |
| author_facet | Singapore Centre for Environmental Life Sciences and Engineering Suryamohan, Kushal Diwanji, Devan Stawiski, Eric W. Gupta, Ravi Miersch, Shane Liu, Jiang Chen, Chao Jiang, Ying-Ping Fellouse, Frederic A. Sathirapongsasuti, J. Fah Albers, Patrick K. Deepak, Tanneeru Saberianfar, Reza Ratan, Aakrosh Washburn, Gavin Mis, Monika Santhosh, Devi Somasekar, Sneha Hiranjith, G. H. Vargas, Derek Mohan, Sangeetha Phalke, Sameer Kuriakose, Boney Antony, Aju Ustav, Mart Schuster, Stephan Christoph Sidhu, Sachdev Junutula, Jagath R. Jura, Natalia Seshagiri, Somasekar |
| author_sort | Suryamohan, Kushal |
| collection | NTU |
| description | COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10-15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus-host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2. |
| first_indexed | 2024-10-01T03:54:31Z |
| format | Journal Article |
| id | ntu-10356/154952 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:54:31Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1549522022-05-28T20:11:42Z Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 Suryamohan, Kushal Diwanji, Devan Stawiski, Eric W. Gupta, Ravi Miersch, Shane Liu, Jiang Chen, Chao Jiang, Ying-Ping Fellouse, Frederic A. Sathirapongsasuti, J. Fah Albers, Patrick K. Deepak, Tanneeru Saberianfar, Reza Ratan, Aakrosh Washburn, Gavin Mis, Monika Santhosh, Devi Somasekar, Sneha Hiranjith, G. H. Vargas, Derek Mohan, Sangeetha Phalke, Sameer Kuriakose, Boney Antony, Aju Ustav, Mart Schuster, Stephan Christoph Sidhu, Sachdev Junutula, Jagath R. Jura, Natalia Seshagiri, Somasekar Singapore Centre for Environmental Life Sciences and Engineering Engineering::Environmental engineering Spike Protein Structural-Analysis COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10-15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus-host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2. Published version D.D. was supported by an F30 fellowship. Grant number: 1F30CA247147. N.J. was supported by the UCSF Quantitative Biosciences Institute Coronavirus Research Group (QCRG) fellowship. A.R. and S.C.S. were supported by SCELSE. 2022-05-27T02:09:08Z 2022-05-27T02:09:08Z 2021 Journal Article Suryamohan, K., Diwanji, D., Stawiski, E. W., Gupta, R., Miersch, S., Liu, J., Chen, C., Jiang, Y., Fellouse, F. A., Sathirapongsasuti, J. F., Albers, P. K., Deepak, T., Saberianfar, R., Ratan, A., Washburn, G., Mis, M., Santhosh, D., Somasekar, S., Hiranjith, G. H., ...Seshagiri, S. (2021). Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. Communications Biology, 4(1), 475-. https://dx.doi.org/10.1038/s42003-021-02030-3 2399-3642 https://hdl.handle.net/10356/154952 10.1038/s42003-021-02030-3 33846513 2-s2.0-85104272913 1 4 475 en Communications Biology © 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
| spellingShingle | Engineering::Environmental engineering Spike Protein Structural-Analysis Suryamohan, Kushal Diwanji, Devan Stawiski, Eric W. Gupta, Ravi Miersch, Shane Liu, Jiang Chen, Chao Jiang, Ying-Ping Fellouse, Frederic A. Sathirapongsasuti, J. Fah Albers, Patrick K. Deepak, Tanneeru Saberianfar, Reza Ratan, Aakrosh Washburn, Gavin Mis, Monika Santhosh, Devi Somasekar, Sneha Hiranjith, G. H. Vargas, Derek Mohan, Sangeetha Phalke, Sameer Kuriakose, Boney Antony, Aju Ustav, Mart Schuster, Stephan Christoph Sidhu, Sachdev Junutula, Jagath R. Jura, Natalia Seshagiri, Somasekar Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title | Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title_full | Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title_fullStr | Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title_full_unstemmed | Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title_short | Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 |
| title_sort | human ace2 receptor polymorphisms and altered susceptibility to sars cov 2 |
| topic | Engineering::Environmental engineering Spike Protein Structural-Analysis |
| url | https://hdl.handle.net/10356/154952 |
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