Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 38, Pages 15265-15270Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310642110
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Funding
- Deutsche Forschungsgemeinschaft [WI3285/2-1]
- European Molecular Biology Organization
- Cluster of Excellence [Exc114/2]
- Estonian Science Foundation [9289]
- European Social Fund Program Mobilitas [MJD144, MJD99]
- Marie Curie FP7-PEOPLE-2011-IEF Postdoctoral Fellowship
- AXA Research Fund Postdoctoral Fellowship
- European Regional Development Fund via the Center of Excellence in Chemical Biology
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Ribosomes are the protein synthesizing factories of the cell, polymerizing polypeptide chains from their constituent amino acids. However, distinct combinations of amino acids, such as polyproline stretches, cannot be efficiently polymerized by ribosomes, leading to translational stalling. The stalled ribosomes are rescued by the translational elongation factor P (EF-P), which by stimulating peptide-bond formation allows translation to resume. Using metabolic stable isotope labeling and mass spectrometry, we demonstrate in vivo that EF-P is important for expression of not only polyproline-containing proteins, but also for specific subsets of proteins containing diprolyl motifs (XPP/PPX). Together with a systematic in vitro and in vivo analysis, we provide a distinct hierarchy of stalling triplets, ranging from strong stallers, such as PPP, DPP, and PPN to weak stallers, such as CPP, PPR, and PPH, all of which are substrates for EF-P. These findings provide mechanistic insight into how the characteristics of the specific amino acid substrates influence the fundamentals of peptide bond formation.
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