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  Large-scale ratcheting in a bacterial DEAH/RHA-type RNA helicase that modulates antibiotics susceptibility

Grass, L. M., Wollenhaupt, J., Barthel, T., Parfentev, I., Urlaub, H., Loll, B., et al. (2021). Large-scale ratcheting in a bacterial DEAH/RHA-type RNA helicase that modulates antibiotics susceptibility. Proceedings of the National Academy of Sciences of the USA, 118(30): e2100370118. doi:10.1073/pnas.2100370118.

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 Creators:
Grass, L. M., Author
Wollenhaupt, J., Author
Barthel, T., Author
Parfentev, I.1, Author           
Urlaub, H.1, Author           
Loll, B., Author
Klauck, E., Author
Antelmann, H., Author
Wahl, M. C., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

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Free keywords: RNA-dependent NTPase/RNA helicase | co-/posttranscriptional gene regulation | antibiotics resistance | X-ray crystallography |structural biology
 Abstract: Many bacteria harbor RNA-dependent nucleoside-triphosphatases of the DEAH/RHA family, whose molecular mechanisms and cellular functions are poorly understood. Here, we show that the Escherichia coli DEAH/RHA protein, HrpA, is an ATP-dependent 3 to 5′ RNA helicase and that the RNA helicase activity of HrpA influences bacterial survival under antibiotics treatment. Limited proteolysis, crys- tal structure analysis, and functional assays showed that HrpA contains an N-terminal DEAH/RHA helicase cassette preceded by a unique N-terminal domain and followed by a large C-terminal region that modulates the helicase activity. Structures of an expanded HrpA helicase cassette in the apo and RNA-bound states in combination with cross-linking/mass spectrometry revealed ratchet-like domain movements upon RNA engagement, much more pronounced than hitherto observed in related eukaryotic DEAH/RHA enzymes. Structure-based functional analyses delineated transient interdomain contact sites that support substrate loading and unwinding, suggest- ing that similar conformational changes support RNA translocation. Consistently, modeling studies showed that analogous dynamic intramolecular contacts are not possible in the related but helicase-inactive RNA-dependent nucleoside-triphosphatase, HrpB. Our results indicate that HrpA may be an interesting target to interfere with bacterial tolerance toward certain antibiotics and suggest possible interfering strategies.

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Language(s): eng - English
 Dates: 2021-07-212021-07-27
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1073/pnas.2100370118
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Title: Proceedings of the National Academy of Sciences of the USA
Source Genre: Journal
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Pages: 12 Volume / Issue: 118 (30) Sequence Number: e2100370118 Start / End Page: - Identifier: ISSN: 0027-8424
ISSN: 1091-6490