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Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway

Kim, Jeong-Mok and Seok, Ok-Hee and Ju, Shinyeong and Heo, Ji-Eun and Yeom, Jeonghun and Kim, Da-Som and Yoo, Joo-Yeon and Varshavsky, Alexander and Lee, Cheolju and Hwang, Cheol-Sang (2018) Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway. Science, 362 (6418). Art. No. eaat0174. ISSN 0036-8075. http://resolver.caltech.edu/CaltechAUTHORS:20181108-125308990

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Abstract

In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. In contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt-formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N-degrons, and identified the Psh1 ubiquitin ligase as the recognition component of this eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/science.aat0174DOIArticle
https://www.sciencemag.org/cgi/content/full/science.aat0174/DC1PublisherSupplementary Materials
ORCID:
AuthorORCID
Kim, Jeong-Mok0000-0002-7223-248X
Ju, Shinyeong0000-0001-5483-4690
Yoo, Joo-Yeon0000-0001-5942-3989
Varshavsky, Alexander0000-0002-4011-258X
Lee, Cheolju0000-0001-8482-4696
Hwang, Cheol-Sang0000-0002-0105-5957
Additional Information:© 2018 American Association for the Advancement of Science. We thank W.-K. Huh (Seoul National University, Seoul, Korea) for yeast deletion library mutants, S. Biggins (Hutchinson Cancer Center, Seattle, WA, USA) for pSB1535 and pSB1541, and R. Sauer (MIT, Cambridge, MA, USA) for AG110A(DE) E. coli. We also thank the present and former members of the Hwang laboratory for their assistance and advice. Supported by grants from the Samsung Science & Technology Foundation (SSTF-BA1401-17) and the BK21 plus program (C.-S.H.), by the NRF grants of the Korean Government (MSIP) NRF-2017M3A9F9030559 (C.L.) and NRF-2017R1A5A1015366 (J.-Y.Y.), and by NIH grants R01GM031530 and R01DK039520 (A.V.). Author contributions: C.-S.H., J.-M.K., J.-Y.Y., C.L., A.V., and other coauthors designed research. J.-M.K., O.-H.S., S.J., J.-E.H., J.Y., D.-S.K. and C.-S.H. performed research, and all coauthors analyzed data. C.-S.H., J.-M.K., C.L. and A.V. wrote the paper. All coauthors declare no competing interests. Data and materials availability: All mass spectrometric data of this study are available in PRIDE database (accession number: PXD010780). All (other) data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.
Funders:
Funding AgencyGrant Number
Samsung Science & Technology FoundationSSTF-BA1401-17
Korean Government ProjectBK21
National Research Foundation of KoreaNRF-2017M3A9F9030559
National Research Foundation of KoreaNRF-2017R1A5A1015366
NIHR01GM031530
NIHR01DK039520
Record Number:CaltechAUTHORS:20181108-125308990
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181108-125308990
Official Citation:Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway. BY JEONG-MOK KIM, OK-HEE SEOK, SHINYEONG JU, JI-EUN HEO, JEONGHUN YEOM, DA-SOM KIM, JOO-YEON YOO, ALEXANDER VARSHAVSKY, CHEOLJU LEE, CHEOL-SANG HWANG. SCIENCE 30 NOV 2018
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90756
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Nov 2018 21:03
Last Modified:03 Dec 2018 17:46

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