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Site-specific release of nascent chains from ribosomes at a sense codon

Lookup NU author(s): Dr Victoriya Doronina, Dr Jeremy Brown

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Abstract

"2A" oligopeptides are autonomous elements containing a D(V/I)EXNPGP motif at the C terminus. Protein synthesis from an open reading frame containing an internal 2A coding sequence yields two separate polypeptides, corresponding to sequences up to and including 2A and those downstream. We show that the 2A reaction occurs in the ribosomal peptidyltransferase center. Ribosomes pause at the end of the 2A coding sequence, over the glycine and proline codons, and the nascent chain up to and including this glycine is released. Translation-terminating release factors eRF1 and eRF3 play key roles in the reaction. On the depletion of eRF1, a greater proportion of ribosomes extend through the 2A coding sequence, yielding the full-length protein. In contrast, impaired eRF3 GTPase activity leads to many ribosomes failing to translate beyond 2A. Further, high-level expression of a 2A peptide-containing protein inhibits the growth of cells compromised for release factor activity and leads to errors in stop codon recognition. We propose that the nascent 2A peptide interacts with ribosomes to drive a highly unusual and specific "termination" reaction, despite the presence of a proline codon in the A site. After this, the majority of ribosomes continue translation, generating the separate downstream product. Copyright © 2008, American Society for Microbiology. All Rights Reserved.


Publication metadata

Author(s): Doronina VA, Wu C, de Felipe P, Sachs MS, Ryan MD, Brown JD

Publication type: Article

Publication status: Published

Journal: Molecular and Cellular Biology

Year: 2008

Volume: 28

Issue: 13

Pages: 4227-4239

Print publication date: 01/07/2008

ISSN (print): 0270-7306

ISSN (electronic): 1067-8824

Publisher: American Society for Microbiology

URL: http://dx.doi.org/10.1128/MCB.00421-08

DOI: 10.1128/MCB.00421-08

PubMed id: 18458056


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Funding

Funder referenceFunder name
Medical Research Council
BB/E009093Biotechnology and Biological Sciences Research Council
BB/E009093/1Biotechnology and Biological Sciences Research Council
BB/E010709/1Biotechnology and Biological Sciences Research Council
BB/E/01070911Biotechnology and Biological Sciences Research Council
C20035Biotechnology and Biological Sciences Research Council
C20418Biotechnology and Biological Sciences Research Council
G117/395Medical Research Council
GM47498NIGMS NIH HHS
R01 GM047498NIGMS NIH HHS

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