A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway
Eukaryotes have evolved the ubiquitin (Ub)/proteasome system to degrade polypeptides. The Ub/proteasome system is one way that cells regulate cytosolic protein and amino acids levels through the recognition and ubiquitination of a protein’s N-terminus via E1, E2, and E3 enzymes. The process by which...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/110605 https://orcid.org/0000-0003-2659-7012 |
| _version_ | 1811085188809097216 |
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| author | Rabideau, Amy Pentelute, Bradley L. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Rabideau, Amy Pentelute, Bradley L. |
| author_sort | Rabideau, Amy |
| collection | MIT |
| description | Eukaryotes have evolved the ubiquitin (Ub)/proteasome system to degrade polypeptides. The Ub/proteasome system is one way that cells regulate cytosolic protein and amino acids levels through the recognition and ubiquitination of a protein’s N-terminus via E1, E2, and E3 enzymes. The process by which the N-terminus stimulates intracellular protein degradation is referred to as the N-end rule. Characterization of the N-end rule has been limited to only the natural l-amino acids. Using a cytosolic delivery platform derived from anthrax lethal toxin, we probed the stability of mixed chirality proteins, containing one d-amino acid on the N-terminus of otherwise all l-proteins. In all cases, we observed that one N-terminal d-amino acid stabilized the cargo protein to proteasomal degradation with respect to the N-end rule. We found that since the mixed chirality proteins were not polyubiquitinated, they evaded N-end-mediated proteasomal degradation. Evidently, a subtle change on the N-terminus of a natural protein can enhance its intracellular lifetime. |
| first_indexed | 2024-09-23T13:05:03Z |
| format | Article |
| id | mit-1721.1/110605 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:05:03Z |
| publishDate | 2017 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1106052022-09-28T11:53:49Z A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway Rabideau, Amy Pentelute, Bradley L. Massachusetts Institute of Technology. Department of Chemistry Rabideau, Amy Pentelute, Bradley L. Eukaryotes have evolved the ubiquitin (Ub)/proteasome system to degrade polypeptides. The Ub/proteasome system is one way that cells regulate cytosolic protein and amino acids levels through the recognition and ubiquitination of a protein’s N-terminus via E1, E2, and E3 enzymes. The process by which the N-terminus stimulates intracellular protein degradation is referred to as the N-end rule. Characterization of the N-end rule has been limited to only the natural l-amino acids. Using a cytosolic delivery platform derived from anthrax lethal toxin, we probed the stability of mixed chirality proteins, containing one d-amino acid on the N-terminus of otherwise all l-proteins. In all cases, we observed that one N-terminal d-amino acid stabilized the cargo protein to proteasomal degradation with respect to the N-end rule. We found that since the mixed chirality proteins were not polyubiquitinated, they evaded N-end-mediated proteasomal degradation. Evidently, a subtle change on the N-terminus of a natural protein can enhance its intracellular lifetime. MIT Faculty Start-up Fund Massachusetts Institute of Technology. Charles E. Reed Faculty Initiative Fund National Science Foundation (U.S.) (CAREER Award CHE-1351807) Damon Runyon Cancer Research Foundation National Science Foundation (U.S.). Graduate Research Fellowship Program 2017-07-10T19:22:29Z 2017-07-10T19:22:29Z 2015-11 2015-09 Article http://purl.org/eprint/type/JournalArticle 2374-7943 2374-7951 http://hdl.handle.net/1721.1/110605 Rabideau, Amy E., and Bradley L. Pentelute. “A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway.” ACS Central Science 1.8 (2015): 423–430. © 2015 American Chemical Society https://orcid.org/0000-0003-2659-7012 en_US http://dx.doi.org/10.1021/acscentsci.5b00308 ACS Central Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | Rabideau, Amy Pentelute, Bradley L. A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title | A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title_full | A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title_fullStr | A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title_full_unstemmed | A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title_short | A d-Amino Acid at the N-Terminus of a Protein Abrogates Its Degradation by the N-End Rule Pathway |
| title_sort | d amino acid at the n terminus of a protein abrogates its degradation by the n end rule pathway |
| url | http://hdl.handle.net/1721.1/110605 https://orcid.org/0000-0003-2659-7012 |
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