Your browser doesn't support javascript.
Deamidation drives molecular aging of the SARS-CoV-2 spike protein receptor-binding motif.
Lorenzo, Ramiro; Defelipe, Lucas A; Aliperti, Lucio; Niebling, Stephan; Custódio, Tânia F; Löw, Christian; Schwarz, Jennifer J; Remans, Kim; Craig, Patricio O; Otero, Lisandro H; Klinke, Sebastián; García-Alai, María; Sánchez, Ignacio E; Alonso, Leonardo G.
  • Lorenzo R; Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET-CICPBA-UNCPBA, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro (FCV-UNCPBA), Tandil, Argentina.
  • Defelipe LA; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany.
  • Aliperti L; Laboratorio de Fisiología de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
  • Niebling S; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; Centre for Structural Systems Biology, Hamburg, Germany.
  • Custódio TF; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; Centre for Structural Systems Biology, Hamburg, Germany.
  • Löw C; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; Centre for Structural Systems Biology, Hamburg, Germany.
  • Schwarz JJ; European Molecular Biology Laboratory, Heidelberg, Germany.
  • Remans K; European Molecular Biology Laboratory, Heidelberg, Germany.
  • Craig PO; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina.
  • Otero LH; Fundación Instituto Leloir, IIBBA-CONICET, and Plataforma Argentina de Biología Estructural y Metabolómica PLABEM, Buenos Aires, Argentina.
  • Klinke S; Fundación Instituto Leloir, IIBBA-CONICET, and Plataforma Argentina de Biología Estructural y Metabolómica PLABEM, Buenos Aires, Argentina.
  • García-Alai M; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; Centre for Structural Systems Biology, Hamburg, Germany.
  • Sánchez IE; Laboratorio de Fisiología de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
  • Alonso LG; Instituto de Nanobiotecnologia (NANOBIOTEC), UBA-CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: lalonso@docente.ffyb.uba.ar.
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.
Subject(s)
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


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