Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization
Abstract
The global pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a severe global health problem because of its rapid spread. Both Ace2 and NRP1 provide initial viral binding sites for SARS-CoV-2. Here, we show that cysteine residues located in the vestigial plasminogen-apple-nematode (PAN) domain of NRP1 are necessary for SARS-CoV-2 spike protein internalization. Mutating novel cysteine residues in the PAN altered NRP1 stability and downstream activation of extracellular signal-regulated kinase (ERK) signaling pathway and impaired its interaction with the spike protein. This resulted in a significant reduction in spike protein abundance in Vero-E6 cells for the original, alpha, and delta SARS-CoV-2 variants even in the presence of the Ace2. Moreover, mutating these cysteine residues in NRP1 significantly lowered its association with Plexin-A1. As the spike protein is a critical component for targeted therapy, our biochemical study may represent a distinct mechanism to develop a path for future therapeutic discovery.
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Science (SC)
- OSTI Identifier:
- 1958900
- Alternate Identifier(s):
- OSTI ID: 1993703
- Grant/Contract Number:
- AC05-00OR22725; 3130F004
- Resource Type:
- Published Article
- Journal Name:
- iScience
- Additional Journal Information:
- Journal Name: iScience Journal Volume: 26 Journal Issue: 4; Journal ID: ISSN 2589-0042
- Publisher:
- Elsevier
- Country of Publication:
- Netherlands
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Pal, Debjani, De, Kuntal, Yates, Timothy B., Kolape, Jaydeep, and Muchero, Wellington. Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization. Netherlands: N. p., 2023.
Web. doi:10.1016/j.isci.2023.106274.
Pal, Debjani, De, Kuntal, Yates, Timothy B., Kolape, Jaydeep, & Muchero, Wellington. Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization. Netherlands. https://doi.org/10.1016/j.isci.2023.106274
Pal, Debjani, De, Kuntal, Yates, Timothy B., Kolape, Jaydeep, and Muchero, Wellington. Sat .
"Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization". Netherlands. https://doi.org/10.1016/j.isci.2023.106274.
@article{osti_1958900,
title = {Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization},
author = {Pal, Debjani and De, Kuntal and Yates, Timothy B. and Kolape, Jaydeep and Muchero, Wellington},
abstractNote = {The global pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a severe global health problem because of its rapid spread. Both Ace2 and NRP1 provide initial viral binding sites for SARS-CoV-2. Here, we show that cysteine residues located in the vestigial plasminogen-apple-nematode (PAN) domain of NRP1 are necessary for SARS-CoV-2 spike protein internalization. Mutating novel cysteine residues in the PAN altered NRP1 stability and downstream activation of extracellular signal-regulated kinase (ERK) signaling pathway and impaired its interaction with the spike protein. This resulted in a significant reduction in spike protein abundance in Vero-E6 cells for the original, alpha, and delta SARS-CoV-2 variants even in the presence of the Ace2. Moreover, mutating these cysteine residues in NRP1 significantly lowered its association with Plexin-A1. As the spike protein is a critical component for targeted therapy, our biochemical study may represent a distinct mechanism to develop a path for future therapeutic discovery.},
doi = {10.1016/j.isci.2023.106274},
journal = {iScience},
number = 4,
volume = 26,
place = {Netherlands},
year = {Sat Apr 01 00:00:00 EDT 2023},
month = {Sat Apr 01 00:00:00 EDT 2023}
}
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