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N-degron and C-degron pathways of protein degradation

Varshavsky, Alexander (2019) N-degron and C-degron pathways of protein degradation. Proceedings of the National Academy of Sciences of the United States of America, 116 (2). pp. 358-366. ISSN 0027-8424.

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This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. N-degrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as “N-degron pathways” and “C-degron pathways.” The former notation replaces the earlier name “N-end rule pathways.” The term “N-end rule” was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an N-degron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.

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Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2018 National Academy of Sciences. Published under the PNAS license. Edited by F. Ulrich Hartl, Max Planck Institute of Biochemistry, Martinsried, Germany, and approved December 3, 2018 (received for review November 5, 2018). PNAS published ahead of print January 8, 2019. Studies in the author’s laboratory are supported by the NIH Grants DK039520 and GM031530. Author contributions: A.V. designed research and wrote the paper. The author declares no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at
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Subject Keywords:degron; proteolysis; ubiquitin; proteasome; N-end rule
Record Number:CaltechAUTHORS:20190108-090142944
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Official Citation:N-degron and C-degron pathways of protein degradation. Alexander Varshavsky. Proceedings of the National Academy of Sciences Jan 2019, 116 (2) 358-366; DOI: 10.1073/pnas.1816596116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92127
Deposited By: Tony Diaz
Deposited On:08 Jan 2019 17:23
Last Modified:09 Jan 2019 17:52

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