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Spike protein fusion loop controls SARS-CoV-2 fusogenicity and infectivity.
Pal, Debnath.
  • Pal D; Indian Institute of Science, Bengaluru 560012, India. Electronic address: dpal@iisc.ac.in.
J Struct Biol ; 213(2): 107713, 2021 06.
Article in English | MEDLINE | ID: covidwho-1117175
Preprint
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Semantic information from SemMedBD (by NLM)
1. Genus: Coronavirus INTERACTS_WITH Murine hepatitis virus
Subject
Genus: Coronavirus
Predicate
INTERACTS_WITH
Object
Murine hepatitis virus
2. Peptides CAUSES modulation by virus of host process
Subject
Peptides
Predicate
CAUSES
Object
modulation by virus of host process
3. Peptides COEXISTS_WITH proline
Subject
Peptides
Predicate
COEXISTS_WITH
Object
proline
4. Genus: Coronavirus INTERACTS_WITH Murine hepatitis virus
Subject
Genus: Coronavirus
Predicate
INTERACTS_WITH
Object
Murine hepatitis virus
5. Peptides CAUSES modulation by virus of host process
Subject
Peptides
Predicate
CAUSES
Object
modulation by virus of host process
6. Peptides COEXISTS_WITH proline
Subject
Peptides
Predicate
COEXISTS_WITH
Object
proline
ABSTRACT
The high SARS-CoV-2 reproductive number driving the COVID-19 pandemic has been a mystery. Our recent in vitro, and in vivo coronaviral pathogenesis studies involving Mouse Hepatitis Virus (MHV-A59) suggest a crucial role for a small host membrane-virus contact initiator region of the Spike protein, called the fusion peptide that enhances the virus fusogenicity and infectivity. Here I study the Spike from five human ß-coronaviruses (HCoV) including the SARS-CoV-2, and MHV-A59 for comparison. The structural and dynamics analyses of the Spike show that its fusion loop spatially organizes three fusion peptides contiguous to each other to synergistically trigger the virus-host membrane fusion process. I propose a Contact Initiation Model based on the architecture of the Spike quaternary structure that explains the obligatory participation of the fusion loop in the initiation of the host membrane contact for the virus fusion process. Among all the HCoV Spikes in this study, SARS-CoV-2 has the most hydrophobic surface and the extent of hydrophobicity correlates with the reproductive number and infectivity of the other HCoV. Comparison between results from standard and replica exchange molecular dynamics reveal the unique physicochemical properties of the SARS-CoV-2 fusion peptides, accrued in part from the presence of consecutive prolines that impart backbone rigidity which aids the virus fusogenicity. The priming of the Spike by its cleavage and subsequent fusogenic conformational transition steered by the fusion loop may be critical for the SARS-CoV-2 spread. The importance of the fusion loop makes it an apt target for anti-virals and vaccine candidates.
Subject(s)
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptides / Protein Structure, Secondary / Spike Glycoprotein, Coronavirus / Protein Domains / SARS-CoV-2 / COVID-19 Type of study: Observational study Topics: Vaccines Limits: Humans Language: English Journal: J Struct Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptides / Protein Structure, Secondary / Spike Glycoprotein, Coronavirus / Protein Domains / SARS-CoV-2 / COVID-19 Type of study: Observational study Topics: Vaccines Limits: Humans Language: English Journal: J Struct Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article