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.

Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.

Details

Title
Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Author
Tayeb-Fligelman, Einav 1 ; Bowler, Jeannette T. 1   VIAFID ORCID Logo  ; Tai, Christen E. 2   VIAFID ORCID Logo  ; Sawaya, Michael R. 3   VIAFID ORCID Logo  ; Jiang, Yi Xiao 1   VIAFID ORCID Logo  ; Garcia, Gustavo 4   VIAFID ORCID Logo  ; Griner, Sarah L. 1   VIAFID ORCID Logo  ; Cheng, Xinyi 1   VIAFID ORCID Logo  ; Salwinski, Lukasz 5   VIAFID ORCID Logo  ; Lutter, Liisa 1 ; Seidler, Paul M. 6 ; Lu, Jiahui 1 ; Rosenberg, Gregory M. 1   VIAFID ORCID Logo  ; Hou, Ke 1   VIAFID ORCID Logo  ; Abskharon, Romany 1 ; Pan, Hope 1   VIAFID ORCID Logo  ; Zee, Chih-Te 7 ; Boyer, David R. 1   VIAFID ORCID Logo  ; Li, Yan 2   VIAFID ORCID Logo  ; Anderson, Daniel H. 1 ; Murray, Kevin A. 1 ; Falcon, Genesis 8 ; Cascio, Duilio 8   VIAFID ORCID Logo  ; Saelices, Lorena 9   VIAFID ORCID Logo  ; Damoiseaux, Robert 10 ; Arumugaswami, Vaithilingaraja 11 ; Guo, Feng 12   VIAFID ORCID Logo  ; Eisenberg, David S. 13   VIAFID ORCID Logo 

1  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Department of Chemistry and Biochemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); Howard Hughes Medical Institute, Los Angeles, USA (GRID:grid.413575.1) (ISNI:0000 0001 2167 1581) 
2  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
3  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Department of Chemistry and Biochemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); Howard Hughes Medical Institute, Los Angeles, USA (GRID:grid.413575.1) (ISNI:0000 0001 2167 1581); UCLA, UCLA-DOE Institute of Genomics and Proteomics, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
4  UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
5  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, UCLA-DOE Institute of Genomics and Proteomics, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
6  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); University of Southern California School of Pharmacy, Department of Pharmacology and Pharmaceutical Sciences, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
7  UCLA, Department of Chemistry and Biochemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
8  UCLA, UCLA-DOE Institute of Genomics and Proteomics, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
9  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); University of Texas Southwestern Medical Center, Center for Alzheimer’s and Neurodegenerative Diseases, Department of Biophysics, Peter O’Donnell Jr. Brain Institute, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
10  UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Department of Bioengineering, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, California NanoSystems Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
11  UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, California NanoSystems Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
12  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
13  UCLA, Department of Biological Chemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, Department of Chemistry and Biochemistry, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); Howard Hughes Medical Institute, Los Angeles, USA (GRID:grid.413575.1) (ISNI:0000 0001 2167 1581); UCLA, UCLA-DOE Institute of Genomics and Proteomics, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); UCLA, California NanoSystems Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
Pages
2379
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-37865-3
ProQuest document ID
2805751335
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.