Announcement

Collapse
No announcement yet.

J Biol Chem . SARS-CoV-2 (COVID-19) Structural and Evolutionary Dynamicome: Insights Into Functional Evolution and Human Genomics

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

  • J Biol Chem . SARS-CoV-2 (COVID-19) Structural and Evolutionary Dynamicome: Insights Into Functional Evolution and Human Genomics


    J Biol Chem


    . 2020 Jun 25;jbc.RA120.014873.
    doi: 10.1074/jbc.RA120.014873. Online ahead of print.
    SARS-CoV-2 (COVID-19) Structural and Evolutionary Dynamicome: Insights Into Functional Evolution and Human Genomics


    Ruchir Gupta 1 , Jacob Charron 2 , Cynthia L Stenger 3 , Jared Painter 3 , Hunter Steward 1 , Taylor W Cook 4 , William Faber 4 , Austin Frisch 1 , Eric Lind 1 , Jacob Bauss 1 , Xiaopeng Li 1 , Olivia Sirpilla 5 , Xavier Soehnlen 5 , Adam Underwood 5 , David Hinds 1 , Michele Morris 6 , Neil Lamb 6 , Joseph A Carcillo 7 , Caleb P Bupp 8 , Bruce D Uhal 1 , Surender Rajasekaran 8 , Jeremy W Prokop 1



    Affiliations

    Abstract

    The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories discover the viral composition and study health outcomes. The small ~30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread, but also enable a robust understanding of all the proteins the viral genome encodes. We have employed protein modeling, molecular dynamic 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 prokoplab.com/vistedd) 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.

    Keywords: COVID-19; RNA virus; human genetics; molecular dynamics; molecular evolution; post-translational modification (PTM); protein structure; receptor structure-function; severe acute respiratory coronavirus 2 (SARS-CoV-2); virus entry.

Working...
X