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Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils.
Tayeb-Fligelman, Einav; Bowler, Jeannette T; Tai, Christen E; Sawaya, Michael R; Jiang, Yi Xiao; Garcia, Gustavo; Griner, Sarah L; Cheng, Xinyi; Salwinski, Lukasz; Lutter, Liisa; Seidler, Paul M; Lu, Jiahui; Rosenberg, Gregory M; Hou, Ke; Abskharon, Romany; Pan, Hope; Zee, Chih-Te; Boyer, David R; Li, Yan; Anderson, Daniel H; Murray, Kevin A; Falcon, Genesis; Cascio, Duilio; Saelices, Lorena; Damoiseaux, Robert; Arumugaswami, Vaithilingaraja; Guo, Feng; Eisenberg, David S.
  • Tayeb-Fligelman E; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Bowler JT; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Tai CE; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Sawaya MR; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
  • Jiang YX; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Garcia G; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Griner SL; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Cheng X; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
  • Salwinski L; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Lutter L; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Seidler PM; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Lu J; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Rosenberg GM; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Hou K; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
  • Abskharon R; UCLA-DOE Institute of Genomics and Proteomics, UCLA, Los Angeles, CA, 90095, USA.
  • Pan H; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Zee CT; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Boyer DR; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Li Y; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
  • Anderson DH; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, 90095, USA.
  • Murray KA; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Falcon G; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Cascio D; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Saelices L; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
  • Damoiseaux R; Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Arumugaswami V; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA.
  • Guo F; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
  • Eisenberg DS; Howard Hughes Medical Institute, Los Angeles, CA, 90095, USA.
Nat Commun ; 14(1): 2379, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2304648
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Nucleocapsid Proteins / COVID-19 / Amyloid Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-37865-3

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Nucleocapsid Proteins / COVID-19 / Amyloid Limits: Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-37865-3