Nature Communications (Apr 2023)
Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
- Einav Tayeb-Fligelman,
- Jeannette T. Bowler,
- Christen E. Tai,
- Michael R. Sawaya,
- Yi Xiao Jiang,
- Gustavo Garcia,
- Sarah L. Griner,
- Xinyi Cheng,
- Lukasz Salwinski,
- Liisa Lutter,
- Paul M. Seidler,
- Jiahui Lu,
- Gregory M. Rosenberg,
- Ke Hou,
- Romany Abskharon,
- Hope Pan,
- Chih-Te Zee,
- David R. Boyer,
- Yan Li,
- Daniel H. Anderson,
- Kevin A. Murray,
- Genesis Falcon,
- Duilio Cascio,
- Lorena Saelices,
- Robert Damoiseaux,
- Vaithilingaraja Arumugaswami,
- Feng Guo,
- David S. Eisenberg
Affiliations
- Einav Tayeb-Fligelman
- Department of Biological Chemistry, UCLA
- Jeannette T. Bowler
- Department of Biological Chemistry, UCLA
- Christen E. Tai
- Department of Biological Chemistry, UCLA
- Michael R. Sawaya
- Department of Biological Chemistry, UCLA
- Yi Xiao Jiang
- Department of Biological Chemistry, UCLA
- Gustavo Garcia
- Department of Molecular and Medical Pharmacology, UCLA
- Sarah L. Griner
- Department of Biological Chemistry, UCLA
- Xinyi Cheng
- Department of Biological Chemistry, UCLA
- Lukasz Salwinski
- Department of Biological Chemistry, UCLA
- Liisa Lutter
- Department of Biological Chemistry, UCLA
- Paul M. Seidler
- Department of Biological Chemistry, UCLA
- Jiahui Lu
- Department of Biological Chemistry, UCLA
- Gregory M. Rosenberg
- Department of Biological Chemistry, UCLA
- Ke Hou
- Department of Biological Chemistry, UCLA
- Romany Abskharon
- Department of Biological Chemistry, UCLA
- Hope Pan
- Department of Biological Chemistry, UCLA
- Chih-Te Zee
- Department of Chemistry and Biochemistry, UCLA
- David R. Boyer
- Department of Biological Chemistry, UCLA
- Yan Li
- Department of Biological Chemistry, UCLA
- Daniel H. Anderson
- Department of Biological Chemistry, UCLA
- Kevin A. Murray
- Department of Biological Chemistry, UCLA
- Genesis Falcon
- UCLA-DOE Institute of Genomics and Proteomics, UCLA
- Duilio Cascio
- UCLA-DOE Institute of Genomics and Proteomics, UCLA
- Lorena Saelices
- Department of Biological Chemistry, UCLA
- Robert Damoiseaux
- Department of Molecular and Medical Pharmacology, UCLA
- Vaithilingaraja Arumugaswami
- Department of Molecular and Medical Pharmacology, UCLA
- Feng Guo
- Department of Biological Chemistry, UCLA
- David S. Eisenberg
- Department of Biological Chemistry, UCLA
- DOI
- https://doi.org/10.1038/s41467-023-37865-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
Abstract The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP’s propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.
