Deamidation drives molecular aging of the SARS-CoV-2 spike protein receptor-binding motif.
J Biol Chem
; 297(4): 101175, 2021 10.
Article
in English
| MEDLINE | ID: covidwho-1401575
ABSTRACT
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 asparagine deamidation of the spike protein, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, which affect 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 protein. Asparagine residues 481 and 501 in the receptor-binding motif deamidate with a half-life of 16.5 and 123 days at 37 °C, respectively. Deamidation is significantly slowed at 4 °C, indicating a strong dependence of spike protein molecular aging on environmental conditions. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the human angiotensin-converting enzyme 2 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 illustrating how deamidation of the spike receptor-binding motif could lead to the accumulation on the virion surface of a nonnegligible chemically diverse spike population in a timescale of days. Our findings provide a potential mechanism for molecular aging of the spike protein with significant consequences for understanding virus infectivity and vaccine development.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Spike Glycoprotein, Coronavirus
/
SARS-CoV-2
Type of study:
Prognostic study
Topics:
Vaccines
Limits:
Humans
Language:
English
Journal:
J Biol Chem
Year:
2021
Document Type:
Article
Affiliation country:
J.jbc.2021.101175
Similar
MEDLINE
...
LILACS
LIS