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  An antimicrobial peptide that inhibits translation by trapping release factor trap.

Florin, T., Maracci, C., Graf, M., Karki, P., Klepacki, D., Berninghausen, O., et al. (2017). An antimicrobial peptide that inhibits translation by trapping release factor trap. Nature Structural and Molecular Biology, 24(9), 752-757. doi:10.1038/nsmb.3439.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-9D83-F Version Permalink: http://hdl.handle.net/21.11116/0000-0001-20E1-C
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 Creators:
Florin, T., Author
Maracci, C.1, Author              
Graf, M., Author
Karki, P.1, Author              
Klepacki, D., Author
Berninghausen, O., Author
Beckmann, R., Author
Vazquez-Laslop, N., Author
Wilson, D. N., Author
Rodnina, M. V.1, Author              
Mankin, A. S, Author
Affiliations:
1Department of Physical Biochemistry, MPI for Biophysical Chemistry, Max Planck Society, ou_578598              

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 Abstract: Apidaecin (Api) belongs to the group of proline-rich antimicrobial peptides (PrAMPs), which are produced by insects and mammals and protect the host from bacterial infection. PrAMPs enter the bacterial cell, bind to the ribosome, and inhibit protein synthesis. Biochemical characterization and recent high-resolution crystal structures have shown that most PrAMPs obstruct the nascent peptide exit tunnel and the peptidyl transferase center in the ribosome and block the initiation step of translation. Despite the lack of the structural information about the Api-bound ribosome, its similarities with the other PrAMPs suggested that Api also inhibits translation initiation. However, our toeprinting experiments in a cell free translation system revealed that Api does not inhibit initiation but, instead, stalls the ribosome at the stop codon. Isolation of Api-resistant E. coli mutants with alterations in class-1 release factors RF1 and RF2, indicated that Api may interfere with the functions of these factors and/or their association with the ribosome. Consistently, our high-resolution cryo-EM structures of ribosomes complexed with Api showed that Api establishes interactions with the ribosomal exit tunnel and with the functionally important conserved GGQ motif of RF1. Furthermore, kinetic studies revealed that Api does not prevent the release of the nascent peptide chain but impedes the dissociation of RF from its binding site in the ribosome. By trapping RF1 and RF2 in the ribosome, Api leads to depletion of free class-1 RFs in the cell, resulting in inhibition of protein synthesis and cell growth arrest. Importantly, the Api-dependent depletion of RFs facilitates premature stop codon read-through. We envision the possibility that similar trapping of RFs on eukaryotic ribosomes could aid in relieving the effects of human genetic diseases caused by premature stop-codons.

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Language(s): eng - English
 Dates: 2017-07-242017-09
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/nsmb.3439
 Degree: -

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Title: Nature Structural and Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 24 (9) Sequence Number: - Start / End Page: 752 - 757 Identifier: -