The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form worldwide. Here, we explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762703 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2020.108630 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population.
Nat Commun
December 2024
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
Highly mutable pathogens generate viral diversity that impacts virulence, transmissibility, treatment, and thwarts acquired immunity. We previously described C19-SPAR-Seq, a high-throughput, next-generation sequencing platform to detect SARS-CoV-2 that we here deployed to systematically profile variant dynamics of SARS-CoV-2 for over 3 years in a large, North American urban environment (Toronto, Canada). Sequencing of the ACE2 receptor binding motif and polybasic furin cleavage site of the Spike gene in over 70,000 patients revealed that population sweeps of canonical variants of concern (VOCs) occurred in repeating wavelets.
View Article and Find Full Text PDFConstruction of an Integration Vector with a Chimeric Signal Peptide for the Expression of Monoclonal Antibodies in Mammalian Cells.
Curr Issues Mol Biol
December 2024
State Scientific Center of Virology and Biotechnology "Vector", Rospotrebnadzor, 630559 Koltsovo, Novosibirsk Region, Russia.
Antibodies are complex protein structures, and producing them using eukaryotic expression systems presents significant challenges. One frequently overlooked aspect of expression vectors is the nucleotide sequence encoding the signal peptide, which plays a pivotal role in facilitating the secretion of recombinant proteins. This study presents the development of an integrative vector, pVEAL3, for expressing full-length recombinant monoclonal antibodies in mammalian cells.
View Article and Find Full Text PDFVariations in Furin SNPs, a Major Concern of SARS-CoV-2 Susceptibility Among Different Populations: An - Approach.
Bioinform Biol Insights
December 2024
Laboratory of Microbial Genomics and Metabolic Engineering, Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh.
COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) had an adverse effect globally because it caused a global pandemic with several million deaths. This virus possesses spike protein that is cleaved or activated by Furin-like protease enzymes occurring by mammalian lung or respiratory cells to enter the mammalian body. The addition of the Furin cleavage site in SARS-CoV-2 makes it a more infectious and emerging virus than its ancestor's viruses.
View Article and Find Full Text PDFPre-pandemic artificial MERS analog of polyfunctional SARS-CoV-2 S1/S2 furin cleavage site domain is unique among spike proteins of genus Betacoronavirus.
BMC Genom Data
December 2024
School of Science, Constructor University, 28759, Bremen, Germany.
Objectives: SARS-CoV-2 spike (S) glycoprotein furin cleavage site is a key determinant of SARS-CoV-2 virulence and COVID-19 pathogencity. Located at the S1/S2 junction, it is unique among sarbecoviruses but frequently found among betacoronaviruses. Recent evidence suggests that this site includes two additional functional motifs: a pat7 nuclear localization signal and two flanking O-glycosites.
View Article and Find Full Text PDFCharacterization of SARS-CoV-2 nucleocapsid protein oligomers.
J Struct Biol
December 2024
Department of Plant Physiology, Institute of Biology, Warsaw University of Life Sciences - SGGW, Warsaw, Poland; Laboratory of Plant Physiology and Photobiology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy; ReGenFix Laboratories, R&D Department, Sardara, Italy. Electronic address:
Oligomers of the SARS-CoV-2 nucleocapsid (N) protein are characterized by pronounced instability resulting in fast degradation. This property likely relates to two contrasting behaviors of the N protein: genome stabilization through a compact nucleocapsid during cell evasion and genome release by nucleocapsid disassembling during infection. In vivo, the N protein forms rounded complexes of high molecular mass from its interaction with the viral genome.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!