Year: 2023
Type: article
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.
Source: Nature Communications
Authors: 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
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: National Science Foundation, U.S. Department of Energy, W. M. Keck Foundation, National Institutes of Health, Office of Science, National Institute on Aging, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, David Geffen School of Medicine, University of California, Los Angeles, Office of Research Infrastructure Programs, National Institutes of Health, California NanoSystems Institute, Argonne National Laboratory, SLAC National Accelerator Laboratory, Common Fund
Awards: G102163711, G107546177, G1104325616, G1212220100, G1313983767, G1505794299, G152310409, G1565084568, Closing the gap between structural biology and translational science for amyloid diseases, G1664757510, G1752326225, Metabolic and epigenetic reprogramming of vital organs in SARS-CoV-2 induced systemic toxicity, G184350170, G2101401529, G2287611682, G2323794368, G2607749399, G262962599, The Stanford-SLAC CryoEM Center, G2849897711, G2887060908, G3075337988, Interplay between AMPK and Hippo Signaling Regulates Ocular Antiviral Response to Zika virus infection, G340565428, G3534087081, G3924411600, G409777406, G4155925329, G4269941704, G4384619604, G4407571571, G4429385918, Development of inhibitors for systemic amyloid diseases, G498139845, G5106849484, G513797252, Pixel Array Detector for Macromolecular Crystallography, G5514976981, G5607048534, G5777747475, Development of inhibitors and diagnostics for amyloid diseases, High-End CryoEM Instrument for the UCLA Electron Imaging Center for Nanomachines, G6848031779, G6918803902, UCLA-DOE INSTITUTE FOR GENOMICS AND PROTEOMICS, G716644868, G7368700025, G7595416162, G7655511949, Reversible Amyloid-Like Fibrils in Membraneless Organelles, G78868261, UCLA-DOE INSTITUTE FOR GENOMICS AND PROTEOMICS, Developing three-dimensional antisense oligonucleotide drugs against COVID-19, CENTER FOR GENOMICS AND PROTEOMICS RESEARCH PROGRAM, G9000012459, G9000051782, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4366985933