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Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway

Chen, Shun-Jia and Kim, Leehyeon and Song, Hyun Kyu and Varshavsky, Alexander (2021) Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway. Proceedings of the National Academy of Sciences of the United States of America, 118 (43). Art. No. e2115430118. ISSN 0027-8424. PMCID PMC8639330. doi:10.1073/pnas.2115430118.

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N-degron pathways are proteolytic systems that recognize proteins bearing N-terminal (Nt) degradation signals (degrons) called N-degrons. Our previous work identified Gid4 as a recognition component (N-recognin) of the Saccharomyces cerevisiae proteolytic system termed the proline (Pro)/N-degron pathway. Gid4 is a subunit of the oligomeric glucose-induced degradation (GID) ubiquitin ligase. Gid4 targets proteins through the binding to their Nt-Pro residue. Gid4 is also required for degradation of Nt-Xaa-Pro (Xaa is any amino acid residue) proteins such as Nt-[Ala-Pro]-Aro10 and Nt-[Ser-Pro]-Pck1, with Pro at position 2. Here, we show that specific aminopeptidases function as components of the Pro/N-degron pathway by removing Nt-Ala or Nt-Ser and yielding Nt-Pro, which can be recognized by Gid4-GID. Nt-Ala is removed by the previously uncharacterized aminopeptidase Fra1. The enzymatic activity of Fra1 is shown to be essential for the GID-dependent degradation of Nt-[Ala-Pro]-Aro10. Fra1 can also trim Nt-[Ala-Pro-Pro-Pro] (stopping immediately before the last Pro) and thereby can target for degradation a protein bearing this Nt sequence. Nt-Ser is removed largely by the mitochondrial/cytosolic/nuclear aminopeptidase Icp55. These advances are relevant to eukaryotes from fungi to animals and plants, as Fra1, Icp55, and the GID ubiquitin ligase are conserved in evolution. In addition to discovering the mechanism of targeting of Xaa-Pro proteins, these insights have also expanded the diversity of substrates of the Pro/N-degron pathway.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Chen, Shun-Jia0000-0002-5489-4930
Kim, Leehyeon0000-0002-1266-7828
Song, Hyun Kyu0000-0001-5684-4059
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2021 National Academy of Sciences. Published under the PNAS license. Contributed by Alexander Varshavsky, September 8, 2021 (sent for review August 21, 2021; reviewed by Ulrich Hartl and William P. Tansey). We thank members of the laboratories of H.K.S. and A.V., particularly Jin Seok Shin for initial preparation and analysis of Pck1, and also Chang-Seok Lee and Cheol-Sang Hwang (Postech, Pohang, Korea) for some of yeast strains used in this study. This work was supported by National Research Foundation of Korea Grants NRF-2020R1A2C3008285 (to H.K.S.) and NRF-2020R1A5A1019023 (to H.K.S.) and by NIH Grants DK039520 (to A.V.) and GM031530 (to A.V.). Data Availability: All relevant data in the paper are entirely available through both text and figures in the manuscript and SI Appendix. Author contributions: S.-J.C., L.K., H.K.S., and A.V. designed research; S.-J.C. and L.K. performed research; S.-J.C., L.K., H.K.S., and A.V. analyzed data; and S.-J.C., L.K., H.K.S., and A.V. wrote the paper. Reviewers: U.H., Max Planck Institute of Biochemistry; and W.P.T., Vanderbilt University. The authors declare no competing interest. This article contains supporting information online at
Funding AgencyGrant Number
National Research Foundation of KoreaNRF-2020R1A2C3008285
National Research Foundation of KoreaNRF-2020R1A5A1019023
Subject Keywords:degron; ubiquitin; aminopeptidase; Fra1; Icp55
Issue or Number:43
PubMed Central ID:PMC8639330
Record Number:CaltechAUTHORS:20211019-154957670
Persistent URL:
Official Citation:Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway. Shun-Jia Chen, Leehyeon Kim, Hyun Kyu Song, Alexander Varshavsky. Proceedings of the National Academy of Sciences Oct 2021, 118 (43) e2115430118; DOI: 10.1073/pnas.2115430118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111542
Deposited By: Tony Diaz
Deposited On:19 Oct 2021 17:03
Last Modified:13 Dec 2021 17:32

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