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SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.
J Biol Chem. 2020 08 14; 295(33):11742-11753.JB

Abstract

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.

Authors+Show Affiliations

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Calvin University, Grand Rapids, Michigan, USA.Department of Mathematics, University of North Alabama, Florence, Alabama, USA.Department of Mathematics, University of North Alabama, Florence, Alabama, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Grand Rapids Community College, Grand Rapids, Michigan, USA.Grand Rapids Community College, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Walsh University, North Canton, Ohio, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Walsh University, North Canton, Ohio, USA.Walsh University, North Canton, Ohio, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.Department of Critical Care Medicine and Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.Department of Physiology, Michigan State University, East Lansing, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Pediatric Intensive Care Unit, Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA. Office of Research, Spectrum Health, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA jprokop54@gmail.com. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

32587094

Citation

Gupta, Ruchir, et al. "SARS-CoV-2 (COVID-19) Structural and Evolutionary Dynamicome: Insights Into Functional Evolution and Human Genomics." The Journal of Biological Chemistry, vol. 295, no. 33, 2020, pp. 11742-11753.
Gupta R, Charron J, Stenger CL, et al. SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics. J Biol Chem. 2020;295(33):11742-11753.
Gupta, R., Charron, J., Stenger, C. L., Painter, J., Steward, H., Cook, T. W., Faber, W., Frisch, A., Lind, E., Bauss, J., Li, X., Sirpilla, O., Soehnlen, X., Underwood, A., Hinds, D., Morris, M., Lamb, N., Carcillo, J. A., Bupp, C., ... Prokop, J. W. (2020). SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics. The Journal of Biological Chemistry, 295(33), 11742-11753. https://doi.org/10.1074/jbc.RA120.014873
Gupta R, et al. SARS-CoV-2 (COVID-19) Structural and Evolutionary Dynamicome: Insights Into Functional Evolution and Human Genomics. J Biol Chem. 2020 08 14;295(33):11742-11753. PubMed PMID: 32587094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics. AU - Gupta,Ruchir, AU - Charron,Jacob, AU - Stenger,Cynthia L, AU - Painter,Jared, AU - Steward,Hunter, AU - Cook,Taylor W, AU - Faber,William, AU - Frisch,Austin, AU - Lind,Eric, AU - Bauss,Jacob, AU - Li,Xiaopeng, AU - Sirpilla,Olivia, AU - Soehnlen,Xavier, AU - Underwood,Adam, AU - Hinds,David, AU - Morris,Michele, AU - Lamb,Neil, AU - Carcillo,Joseph A, AU - Bupp,Caleb, AU - Uhal,Bruce D, AU - Rajasekaran,Surender, AU - Prokop,Jeremy W, Y1 - 2020/06/25/ PY - 2020/06/22/received PY - 2020/06/23/revised PY - 2020/6/27/pubmed PY - 2020/8/28/medline PY - 2020/6/27/entrez KW - COVID-19 KW - RNA virus KW - human genetics KW - molecular dynamics KW - molecular evolution KW - post-translational modification (PTM) KW - protein structure KW - receptor structure-function KW - severe acute respiratory coronavirus 2 (SARS-CoV-2) KW - virus entry SP - 11742 EP - 11753 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 295 IS - 33 N2 - The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/32587094/SARS_CoV_2__COVID_19__structural_and_evolutionary_dynamicome:_Insights_into_functional_evolution_and_human_genomics_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=32587094 DB - PRIME DP - Unbound Medicine ER -