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Force-dependent stimulation of RNA unwinding by SARS-CoV-2 nsp13 helicase.
Mickolajczyk, Keith J; Shelton, Patrick M M; Grasso, Michael; Cao, Xiaocong; Warrington, Sara E; Aher, Amol; Liu, Shixin; Kapoor, Tarun M.
  • Mickolajczyk KJ; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York.
  • Shelton PMM; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York.
  • Grasso M; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York.
  • Cao X; Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, New York; Laboratory of Structural Immunology, University of Science and Technology of China, Hefei, Anhui, China.
  • Warrington SE; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York.
  • Aher A; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York.
  • Liu S; Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, New York. Electronic address: shixinliu@rockefeller.edu.
  • Kapoor TM; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York. Electronic address: kapoor@rockefeller.edu.
Biophys J ; 120(6): 1020-1030, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-987186
Preprint
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ABSTRACT
The superfamily 1 helicase nonstructural protein 13 (nsp13) is required for SARS-CoV-2 replication. The mechanism and regulation of nsp13 has not been explored at the single-molecule level. Specifically, force-dependent unwinding experiments have yet to be performed for any coronavirus helicase. Here, using optical tweezers, we find that nsp13 unwinding frequency, processivity, and velocity increase substantially when a destabilizing force is applied to the RNA substrate. These results, along with bulk assays, depict nsp13 as an intrinsically weak helicase that can be activated >50-fold by piconewton forces. Such force-dependent behavior contrasts the known behavior of other viral monomeric helicases, such as hepatitis C virus NS3, and instead draws stronger parallels to ring-shaped helicases. Our findings suggest that mechanoregulation, which may be provided by a directly bound RNA-dependent RNA polymerase, enables on-demand helicase activity on the relevant polynucleotide substrate during viral replication.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: DNA, Viral / RNA, Viral / Viral Nonstructural Proteins / RNA Helicases / SARS-CoV-2 / Methyltransferases Language: English Journal: Biophys J Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: DNA, Viral / RNA, Viral / Viral Nonstructural Proteins / RNA Helicases / SARS-CoV-2 / Methyltransferases Language: English Journal: Biophys J Year: 2021 Document Type: Article