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RNA conformational propensities determine cellular activity.

Publication ,  Journal Article
Ken, ML; Roy, R; Geng, A; Ganser, LR; Manghrani, A; Cullen, BR; Schulze-Gahmen, U; Herschlag, D; Al-Hashimi, HM
Published in: Nature
May 2023

Cellular processes are the product of interactions between biomolecules, which associate to form biologically active complexes1. These interactions are mediated by intermolecular contacts, which if disrupted, lead to alterations in cell physiology. Nevertheless, the formation of intermolecular contacts nearly universally requires changes in the conformations of the interacting biomolecules. As a result, binding affinity and cellular activity crucially depend both on the strength of the contacts and on the inherent propensities to form binding-competent conformational states2,3. Thus, conformational penalties are ubiquitous in biology and must be known in order to quantitatively model binding energetics for protein and nucleic acid interactions4,5. However, conceptual and technological limitations have hindered our ability to dissect and quantitatively measure how conformational propensities affect cellular activity. Here we systematically altered and determined the propensities for forming the protein-bound conformation of HIV-1 TAR RNA. These propensities quantitatively predicted the binding affinities of TAR to the RNA-binding region of the Tat protein and predicted the extent of HIV-1 Tat-dependent transactivation in cells. Our results establish the role of ensemble-based conformational propensities in cellular activity and reveal an example of a cellular process driven by an exceptionally rare and short-lived RNA conformational state.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 2023

Volume

617

Issue

7962

Start / End Page

835 / 841

Location

England

Related Subject Headings

  • tat Gene Products, Human Immunodeficiency Virus
  • Transcriptional Activation
  • RNA, Viral
  • Nucleic Acid Conformation
  • HIV-1
  • HIV Long Terminal Repeat
  • General Science & Technology
 

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Ken, M. L., Roy, R., Geng, A., Ganser, L. R., Manghrani, A., Cullen, B. R., … Al-Hashimi, H. M. (2023). RNA conformational propensities determine cellular activity. Nature, 617(7962), 835–841. https://doi.org/10.1038/s41586-023-06080-x
Ken, Megan L., Rohit Roy, Ainan Geng, Laura R. Ganser, Akanksha Manghrani, Bryan R. Cullen, Ursula Schulze-Gahmen, Daniel Herschlag, and Hashim M. Al-Hashimi. “RNA conformational propensities determine cellular activity.Nature 617, no. 7962 (May 2023): 835–41. https://doi.org/10.1038/s41586-023-06080-x.
Ken ML, Roy R, Geng A, Ganser LR, Manghrani A, Cullen BR, et al. RNA conformational propensities determine cellular activity. Nature. 2023 May;617(7962):835–41.
Ken, Megan L., et al. “RNA conformational propensities determine cellular activity.Nature, vol. 617, no. 7962, May 2023, pp. 835–41. Pubmed, doi:10.1038/s41586-023-06080-x.
Ken ML, Roy R, Geng A, Ganser LR, Manghrani A, Cullen BR, Schulze-Gahmen U, Herschlag D, Al-Hashimi HM. RNA conformational propensities determine cellular activity. Nature. 2023 May;617(7962):835–841.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 2023

Volume

617

Issue

7962

Start / End Page

835 / 841

Location

England

Related Subject Headings

  • tat Gene Products, Human Immunodeficiency Virus
  • Transcriptional Activation
  • RNA, Viral
  • Nucleic Acid Conformation
  • HIV-1
  • HIV Long Terminal Repeat
  • General Science & Technology