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 Jr; 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

doi:10.1038/s41467-023-37865-3

Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

Nat Commun. 2023 Apr 25;14(1):2379. doi: 10.1038/s41467-023-37865-3.

Authors

Einav Tayeb-Fligelman^{1

2

3

4}, Jeannette T Bowler^{1

2

3

4}, Christen E Tai^{1

2}, Michael R Sawaya^{1

2

3

4

5}, Yi Xiao Jiang^{1

2

3

4}, Gustavo Garcia Jr⁶, Sarah L Griner^{1

2

3

4}, Xinyi Cheng^{1

2

3

4}, Lukasz Salwinski^{1

2

5}, Liisa Lutter^{1

2

3

4}, Paul M Seidler^{1

2

7}, Jiahui Lu^{1

2

3

4}, Gregory M Rosenberg^{1

2

3

4}, Ke Hou^{1

2

3

4}, Romany Abskharon^{1

2

3

4}, Hope Pan^{1

2

3

4}, Chih-Te Zee³, David R Boyer^{1

2

3

4}, Yan Li^{1

2}, Daniel H Anderson^{1

2

3

4}, Kevin A Murray^{1

2

3

4}, Genesis Falcon⁵, Duilio Cascio⁵, Lorena Saelices^{1

2

8}, Robert Damoiseaux^{6

9

10

11

12}, Vaithilingaraja Arumugaswami^{6

10

11}, Feng Guo^{1

2

12}, David S Eisenberg^{13

14

15

16

17

18}

Affiliations

¹ Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
² Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
³ Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
⁴ Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
⁵ UCLA-DOE Institute of Genomics and Proteomics, UCLA, Los Angeles, CA, 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, 90095, USA.
⁷ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, CA, 90089-9121, USA.
⁸ Center for Alzheimer's and Neurodegenerative Diseases, Department of Biophysics, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁹ Department of Bioengineering, UCLA, Los Angeles, CA, 90095, USA.
¹⁰ California NanoSystems Institute, UCLA, Los Angeles, CA, 90095, USA.
¹¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA.
¹² Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA.
¹³ Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA. [email protected].
¹⁴ Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA. [email protected].
¹⁵ Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA. [email protected].
¹⁶ Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA. [email protected].
¹⁷ UCLA-DOE Institute of Genomics and Proteomics, UCLA, Los Angeles, CA, 90095, USA. [email protected].
¹⁸ California NanoSystems Institute, UCLA, Los Angeles, CA, 90095, USA. [email protected].

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Amyloid* / metabolism
Amyloidogenic Proteins
COVID-19*
Coronavirus Nucleocapsid Proteins*
Humans
Nucleocapsid Proteins
Peptides / chemistry
Protein Domains
SARS-CoV-2 / metabolism

Substances

Amyloid
Amyloidogenic Proteins
Nucleocapsid Proteins
Peptides
Coronavirus Nucleocapsid Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding