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Formyl-methionine as a degradation signal at the N-termini of bacterial proteins

Piatkov, Konstantin and Vu, Tri and Hwang, Cheol-Sang and Varshavsky, Alexander (2015) Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. Microbial Cell, 2 (10). pp. 376-393. ISSN 2311-2638. PMCID PMC4745127. http://resolver.caltech.edu/CaltechAUTHORS:20160509-130856265

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Abstract

In bacteria, all nascent proteins bear the pretranslationally formed N-terminal formyl-methionine (fMet) residue. The fMet residue is cotranslationally deformylated by a ribosome-associated deformylase. The formylation of N-terminal Met in bacterial proteins is not strictly essential for either translation or cell viability. Moreover, protein synthesis by the cytosolic ribosomes of eukaryotes does not involve the formylation of N-terminal Met. What, then, is the main biological function of this metabolically costly, transient, and not strictly essential modification of N‑terminal Met, and why has Met formylation not been eliminated during bacterial evolution? One possibility is that the similarity of the formyl and acetyl groups, their identical locations in N‑terminally formylated (Nt‑formylated) and Nt-acetylated proteins, and the recently discovered proteolytic function of Nt-acetylation in eukaryotes might also signify a proteolytic role of Nt‑formylation in bacteria. We addressed this hypothesis about fMet‑based degradation signals, termed fMet/N-degrons, using specific E. coli mutants, pulse-chase degradation assays, and protein reporters whose deformylation was altered, through site-directed mutagenesis, to be either rapid or relatively slow. Our findings strongly suggest that the formylated N-terminal fMet can act as a degradation signal, largely a cotranslational one. One likely function of fMet/N-degrons is the control of protein quality. In bacteria, the rate of polypeptide chain elongation is nearly an order of magnitude higher than in eukaryotes. We suggest that the faster emergence of nascent proteins from bacterial ribosomes is one mechanistic and evolutionary reason for the pretranslational design of bacterial fMet/N‑degrons, in contrast to the cotranslational design of analogous Ac/N‑degrons in eukaryotes.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.15698/mic2015.10.231DOIArticle
http://microbialcell.com/researcharticles/formyl-methionine-as-a-degradation-signal-at-the-n-termini-of-bacterial-proteins/PublisherArticle
http://microbialcell.com/wordpress/wp-content/uploads/2015/09/2015A-Piatkov-Microbial-Cell-Suppl.pdfPublisherSupplemental Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745127/PubMed CentralArticle
ORCID:
AuthorORCID
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2015 Piatkov et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged. We thank Bernd Bukau (ZMBH, Heidelberg, Germany), Vladimir Ksenzenko (Institute of Protein Research, Pushchino, Russia), and Didier Mazel (Institut Pasteur, Paris, France) for gifts of plasmids and E. coli strains. We thank Shu-ou Shan (Caltech, Pasadena, USA) for a discussion of our findings. We also thank David Chan, Michael Elowitz, Brandon Wadas (Caltech), Daniel Finley (Harvard Medical School, Boston, USA), Gholson Lyon (Cold Spring Harbor Laboratory, Cold Spring Harbor, USA), and William Tansey (Vanderbilt University, Nashville, USA) for comments on the manuscript. We are grateful to members of the Varshavsky laboratory for their interest and helpful discussions. This work was supported by grants to A.V. from the National Institutes of Health (DK039520 and GM031530). The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHDK039520
NIHGM031530
PubMed Central ID:PMC4745127
Record Number:CaltechAUTHORS:20160509-130856265
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160509-130856265
Official Citation:Konstantin I. Piatkov, Tri T. M. Vu, Cheol- Sang Hwang, and Alexander Varshavsky (2015). Formylmethionine as a degradation signal at the N-termini of bacterial proteins. Microbial Cell 2(10): 376-393. doi: 10.15698/mic2015.10.231
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66775
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 May 2016 20:17
Last Modified:15 Nov 2017 00:16

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