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Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling

Oh, Jang-Hyun and Hyun, Ju-Yeon and Chen, Shun-Jia and Varshavsky, Alexander (2020) Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling. Proceedings of the National Academy of Sciences of the United States of America, 117 (20). pp. 10778-10788. ISSN 0027-8424. PMCID PMC7245096. https://resolver.caltech.edu/CaltechAUTHORS:20200505-133829988

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Abstract

The Arg/N-degron pathway targets proteins for degradation by recognizing their N-terminal (Nt) residues. If a substrate bears, for example, Nt-Asn, its targeting involves deamidation of Nt-Asn, arginylation of resulting Nt-Asp, binding of resulting (conjugated) Nt-Arg to the UBR1-RAD6 E3-E2 ubiquitin ligase, ligase-mediated synthesis of a substrate-linked polyubiquitin chain, its capture by the proteasome, and substrate’s degradation. We discovered that the human Nt-Asn–specific Nt-amidase NTAN1, Nt-Gln–specific Nt-amidase NTAQ1, arginyltransferase ATE1, and the ubiquitin ligase UBR1-UBE2A/B (or UBR2-UBE2A/B) form a complex in which NTAN1 Nt-amidase binds to NTAQ1, ATE1, and UBR1/UBR2. In addition, NTAQ1 Nt-amidase and ATE1 arginyltransferase also bind to UBR1/UBR2. In the yeast Saccharomyces cerevisiae, the Nt-amidase, arginyltransferase, and the double-E3 ubiquitin ligase UBR1-RAD6/UFD4-UBC4/5 are shown to form an analogous targeting complex. These complexes may enable substrate channeling, in which a substrate bearing, for example, Nt-Asn, would be captured by a complex-bound Nt-amidase, followed by sequential Nt modifications of the substrate and its polyubiquitylation at an internal Lys residue without substrate’s dissociation into the bulk solution. At least in yeast, the UBR1/UFD4 ubiquitin ligase interacts with the 26S proteasome, suggesting an even larger Arg/N-degron–targeting complex that contains the proteasome as well. In addition, specific features of protein-sized Arg/N-degron substrates, including their partly sequential and partly nonsequential enzymatic modifications, led us to a verifiable concept termed “superchanneling.” In superchanneling, the synthesis of a substrate-linked poly-Ub chain can occur not only after a substrate’s sequential Nt modifications, but also before them, through a skipping of either some or all of these modifications within a targeting complex.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2003043117DOIArticle
https://www.pnas.org/content/suppl/2020/05/03/2003043117.DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7245096/PubMed CentralArticle
ORCID:
AuthorORCID
Oh, Jang-Hyun0000-0002-2053-7468
Hyun, Ju-Yeon0000-0002-5526-9651
Chen, Shun-Jia0000-0002-5489-4930
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2020 National Academy of Sciences. Published under the PNAS license. Contributed by Alexander Varshavsky, February 28, 2020 (sent for review February 18, 2020; reviewed by Thomas Arnesen and William P. Tansey. PNAS first published May 4, 2020. We thank current and former members of the A.V. laboratory for their advice and assistance. This work was supported by the NIH Grants 1R01DK039520 and 1R01GM031530 (to A.V.). Data Availability: All relevant data in the paper are entirely available through both text and figures, in the main text and SI Appendix. Author contributions: J.-H.O., J.-Y.H., S.-J.C., and A.V. designed research; J.-H.O., J.-Y.H., and S.-J.C. performed research; J.-H.O., J.-Y.H., S.-J.C., and A.V. analyzed data; and J.-H.O., J.-Y.H., S.-J.C., and A.V. wrote the paper. Reviewers: T.A., University of Bergen; and W.P.T., Vanderbilt University. The authors declare no competing interest. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2003043117/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIH1R01DK039520
NIH1R01GM031530
Subject Keywords:degron; channeling; superchanneling; ubiquitin; degradation
Issue or Number:20
PubMed Central ID:PMC7245096
Record Number:CaltechAUTHORS:20200505-133829988
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200505-133829988
Official Citation:Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling. Jang-Hyun Oh, Ju-Yeon Hyun, Shun-Jia Chen, Alexander Varshavsky. Proceedings of the National Academy of Sciences, May 2020, 117 (20) 10778-10798; DOI: 10.1073/pnas.2003043117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103004
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 May 2020 20:46
Last Modified:08 Jun 2020 16:48

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