Dataset Information

Deamidation drives molecular aging of the SARS-CoV-2 spike receptor-binding motif

ABSTRACT: The spike is the main protein component of the SARS-CoV-2 virion surface. The spike receptor-binding motif mediates recognition of the hACE2 receptor, a critical infection step, and is the preferential target for spike-neutralizing antibodies. Post-translational modifications of the spike receptor-binding motif can modulate viral infectivity and immune response. We studied the spike protein searching for asparagine deamidation, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, affecting both the protein backbone and its charge. We used computational prediction and biochemical experiments to identify five deamidation hotspots in the SARS-CoV-2 spike. Asparagine residues 481 and 501 from the receptor-binding motif deamidate with a half-time of 16.5 and 123 days at 37 °C, respectively. Deamidation is significantly slowed down at 4 °C, pointing at a strong dependence of spike molecular aging on the environmental conditions. We demonstrate that topological constraints drive the conservation of deamidation hotspots among Sarbecoviruses spike proteins. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the hACE2 receptor more than 3.5-fold, yet its high conservation pattern suggests some positive effect on viral fitness. We propose a model for deamidation of the full SARS-CoV-2 virion that illustrates how deamidation of the spike receptor-binding motif leads to the accumulation on the virion surface of a non-negligible chemically diverse spike population in a timescale of days. Our findings provide a mechanism for molecular aging of the spike, with significant consequences for understanding virus infectivity and vaccine development.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Severe Acute Respiratory Syndrome Coronavirus 2

DISEASE(S): Covid-19

SUBMITTER: Jennifer Schwarz

LAB HEAD: Leonardo G.Alonso

PROVIDER: PXD028071 | Pride | 2022-02-15

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	MaxQuant_1.6.17.0.zip	Other
	Zelda_201009_P1421_JS_LD_10d37C_GluCTry.index	Other
	Zelda_201009_P1421_JS_LD_10d37C_GluCTry.raw	Raw
	Zelda_201009_P1421_JS_LD_10d4C_GluCTry.index	Other
	Zelda_201009_P1421_JS_LD_10d4C_GluCTry.raw	Raw

Items per page:

1 - 5 of 154

Publications

Deamidation drives molecular aging of the SARS-CoV-2 spike protein receptor-binding motif.

Lorenzo Ramiro R Defelipe Lucas A LA Aliperti Lucio L Niebling Stephan S Custódio Tânia F TF Löw Christian C Schwarz Jennifer J JJ Remans Kim K Craig Patricio O PO Otero Lisandro H LH Klinke Sebastián S García-Alai María M Sánchez Ignacio E IE Alonso Leonardo G LG

The Journal of biological chemistry 20210907 4

The spike protein is the main protein component of the SARS-CoV-2 virion surface. The spike receptor-binding motif mediates recognition of the human angiotensin-converting enzyme 2 receptor, a critical step in infection, and is the preferential target for spike-neutralizing antibodies. Posttranslational modifications of the spike receptor-binding motif have been shown to modulate viral infectivity and host immune response, but these modifications are still being explored. Here we studied asparag ...[more]

PMID: 34499924

Similar Datasets

Project description:Rapid emergence of antigenic distinct SARS-CoV-2 variants implies a greater risk of reinfection as viruses can escape neutralizing antibodies induced by vaccination or previous viral exposure. Disease severity during COVID-19 depends on many variables such as age-related comorbidities, host immune status and genetic variation. The host immune response during infection with SARS-CoV-2 may contribute to disease severity, which can range from asymptomatic to severe with fatal outcome. Furthermore, the extent of host immune response activation may rely on underlying genetic predisposition for disease or protection. To address these questions, we performed immune profiling studies in mice with different genetic backgrounds - transgenic K18-hACE2 and wild-type 129S1 mice – subjected to reinfection with the severe disease-causing SARS-CoV-2 B.1.351 variant, 30 days after experimental milder BA.1 infection. BA.1 preinfection conferred protection against B.1.351-induced morbidity in K18-hACE2 mice but aggravated disease in 129S1 mice. We found that he cytokine/chemokine profile in B.1.351 re-infected 129S1mice is similar to that during severe SARS-CoV-2 infection in humans and is characterized by a much higher level of IL-10, IL-1β, IL-18 and IFN-γ , whereas in B.1.351 re-infected K18-hACE2 mice, the cytokine profile echoes the signature of naïve mice undergoing viral infection for the first time. Interestingly, the enhanced pathology observed in 129S1 mice upon reinfection cannot be attributed to a less efficient induction of adaptive immune responses to the initial BA.1 infection, as both K18-hACE2 and 129S1 mice exhibited similar B and T cell responses at 30 DPI against BA.1, with similar anti-BA.1 or B.1.351 spike-specific ELISA binding titers, levels of germinal center B-cells, and SARS-CoV-2-Spike specific tissue-resident T-cells. Long-term effects of BA.1 infection are associated with differential transcriptional changes in bronchoalveolar lavage-derived CD11c+ immune cells from K18-hACE2 and 129S1, with K18-hACE2 CD11c+ cells showing a strong antiviral defense gene expression profile whereas 129S1 CD11c+ cells showed a more pro-inflammatory response. In conclusion, initial infection with BA.1 induces cross-reactive adaptive immune responses in both K18-hACE2 and 129S1 mice, however the different disease outcome of reinfection seems to be driven by differential responses of CD11c+ cells in the alveolar space.