Your browser doesn't support javascript.
Engineered disulfide reveals structural dynamics of locked SARS-CoV-2 spike.
Qu, Kun; Chen, Qiuluan; Ciazynska, Katarzyna A; Liu, Banghui; Zhang, Xixi; Wang, Jingjing; He, Yujie; Guan, Jiali; He, Jun; Liu, Tian; Zhang, Xiaofei; Carter, Andrew P; Xiong, Xiaoli; Briggs, John A G.
  • Qu K; Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
  • Chen Q; Infectious Diseases Translational Research Programme, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Ciazynska KA; Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, China.
  • Liu B; Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
  • Zhang X; The State Key Laboratory of Respiratory Disease (SKLRD), CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guang
  • Wang J; The State Key Laboratory of Respiratory Disease (SKLRD), CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guang
  • He Y; The State Key Laboratory of Respiratory Disease (SKLRD), CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guang
  • Guan J; Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, China.
  • He J; Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, China.
  • Liu T; Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, China.
  • Zhang X; The State Key Laboratory of Respiratory Disease (SKLRD), CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guang
  • Carter AP; Center for Proteomics and Metabolomics, Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
  • Xiong X; Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, China.
  • Briggs JAG; The State Key Laboratory of Respiratory Disease (SKLRD), CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guang
PLoS Pathog ; 18(7): e1010583, 2022 07.
Article in English | MEDLINE | ID: covidwho-1974332
ABSTRACT
The spike (S) protein of SARS-CoV-2 has been observed in three distinct pre-fusion conformations locked, closed and open. Of these, the function of the locked conformation remains poorly understood. Here we engineered a SARS-CoV-2 S protein construct "S-R/x3" to arrest SARS-CoV-2 spikes in the locked conformation by a disulfide bond. Using this construct we determined high-resolution structures confirming that the x3 disulfide bond has the ability to stabilize the otherwise transient locked conformations. Structural analyses reveal that wild-type SARS-CoV-2 spike can adopt two distinct locked-1 and locked-2 conformations. For the D614G spike, based on which all variants of concern were evolved, only the locked-2 conformation was observed. Analysis of the structures suggests that rigidified domain D in the locked conformations interacts with the hinge to domain C and thereby restrains RBD movement. Structural change in domain D correlates with spike conformational change. We propose that the locked-1 and locked-2 conformations of S are present in the acidic high-lipid cellular compartments during virus assembly and egress. In this model, release of the virion into the neutral pH extracellular space would favour transition to the closed or open conformations. The dynamics of this transition can be altered by mutations that modulate domain D structure, as is the case for the D614G mutation, leading to changes in viral fitness. The S-R/x3 construct provides a tool for the further structural and functional characterization of the locked conformations of S, as well as how sequence changes might alter S assembly and regulation of receptor binding domain dynamics.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010583

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: PLoS Pathog Year: 2022 Document Type: Article Affiliation country: Journal.ppat.1010583