Disease-linked mutations cause exposure of a protein quality control degron
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
More than half of disease-causing missense variants are thought to lead to protein degradation, but the molecular mechanism of how these variants are recognized by the cell remains enigmatic. Degrons are stretches of amino acids that help mediate recognition by E3 ligases and thus confer protein degradation via the ubiquitin-proteasome system. While degrons that mediate controlled degradation of, for example, signaling components and cell-cycle regulators are well described, so-called protein-quality-control degrons that mediate the degradation of destabilized proteins are poorly understood. Here, we show that disease-linked dihydrofolate reductase (DHFR) missense variants are structurally destabilized and chaperone-dependent proteasome targets. We find two regions in DHFR that act as degrons, and the proteasomal turnover of one of these was dependent on the molecular chaperone Hsp70. Structural analyses by nuclear magnetic resonance (NMR) and hydrogen/deuterium exchange revealed that this degron is buried in wild-type DHFR but becomes transiently exposed in the disease-linked missense variants.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Structure |
| Vol/bind | 30 |
| Udgave nummer | 9 |
| Sider (fra-til) | 1245-1253.e5 |
| ISSN | 0969-2126 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
The authors thank Anne-Marie Lauridsen for technical assistance and Dr. Michael Askvad Sørensen for assistance with DHFR purification. The present work was funded by the Novo Nordisk Foundation ( https://novonordiskfonden.dk ) challenge program PRISM (to K.L.-L., A.S., and R.H.-P.), NNF18OC0052441 (to R.H.-P.), and NNF18OC0032996 (to K.T.); the Lundbeck Foundation ( https://www.lundbeckfonden.com ) R272-2017-452 and R209-2015-3283 (to A.S.); and Danish Council for Independent Research (Det Frie Forskningsråd) ( https://dff.dk ) 7014-00039B (to R.H.-P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
The authors thank Anne-Marie Lauridsen for technical assistance and Dr. Michael Askvad Sørensen for assistance with DHFR purification. The present work was funded by the Novo Nordisk Foundation (https://novonordiskfonden.dk) challenge program PRISM (to K.L.-L. A.S. and R.H.-P.), NNF18OC0052441 (to R.H.-P.), and NNF18OC0032996 (to K.T.); the Lundbeck Foundation (https://www.lundbeckfonden.com) R272-2017-452 and R209-2015-3283 (to A.S.); and Danish Council for Independent Research (Det Frie Forskningsråd) (https://dff.dk) 7014-00039B (to R.H.-P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. C.K. M.M. S.L.-L. A.C. M.R.W. S.V.N. S.L. H.K.M.I. and A.S. performed the experiments, C.K. T.R. A.S. K.L.-L. K.T. and R.H.-P. analyzed the data. T.R. K.L.-L. and R.H.-P. conceived the study. C.K. and R.H.-P. wrote the paper. The authors declare no competing interests.
Publisher Copyright:
© 2022 Elsevier Ltd
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