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Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction
Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3’s proteasomal degradation. Many E3s have evolved means to avoi...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608492/ https://www.ncbi.nlm.nih.gov/pubmed/23363599 http://dx.doi.org/10.1091/mbc.E12-11-0811 |
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author | Fredrickson, Eric K. Clowes Candadai, Sarah V. Tam, Cheuk Ho Gardner, Richard G. |
author_facet | Fredrickson, Eric K. Clowes Candadai, Sarah V. Tam, Cheuk Ho Gardner, Richard G. |
author_sort | Fredrickson, Eric K. |
collection | PubMed |
description | Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3’s proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination, including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate-binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions; thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1’s target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, and thus the that feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways in which E3s protect themselves from autoubiquitination. |
format | Online Article Text |
id | pubmed-3608492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-36084922013-06-16 Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction Fredrickson, Eric K. Clowes Candadai, Sarah V. Tam, Cheuk Ho Gardner, Richard G. Mol Biol Cell Articles Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3’s proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination, including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate-binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions; thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1’s target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, and thus the that feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways in which E3s protect themselves from autoubiquitination. The American Society for Cell Biology 2013-04-01 /pmc/articles/PMC3608492/ /pubmed/23363599 http://dx.doi.org/10.1091/mbc.E12-11-0811 Text en © 2013 Fredrickson et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell BD; are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Fredrickson, Eric K. Clowes Candadai, Sarah V. Tam, Cheuk Ho Gardner, Richard G. Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title | Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title_full | Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title_fullStr | Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title_full_unstemmed | Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title_short | Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
title_sort | means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608492/ https://www.ncbi.nlm.nih.gov/pubmed/23363599 http://dx.doi.org/10.1091/mbc.E12-11-0811 |
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