Mouse ACE2 receptor bound to SARS-CoV-2 variant Beta Spike
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ABSTRACT:
SUBMITTER: Kelvin Lau
PROVIDER: EMPIAR-11181 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
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Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding.
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Project description:The SARS-CoV-2 betacoronavirus uses its highly glycosylated trimeric Spike protein to bind to the cell surface receptor angiotensin converting enzyme 2 (ACE2) glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatics analyses of natural variants and with existing 3D structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein both alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation. Taken together, these data can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.
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Project description:The current COVID-19 pandemic is caused by the SARS-CoV-2 betacoronavirus, which utilizes its highly glycosylated trimeric Spike protein to bind to the cell surface receptor ACE2 glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatic analyses of natural variants and with existing 3D-structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation that, taken together, can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.
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