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Nat Chem Biol. 2015 Sep;11(9):713-20. doi: 10.1038/nchembio.1869. Epub 2015 Jul 27.

Tunable and reversible drug control of protein production via a self-excising degron.

Author information

1
Department of Biology, Stanford University, Stanford, California, USA.
2
Department of Pediatrics, Stanford University, Stanford, California, USA.
3
Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
4
Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
5
1] Department of Pediatrics, Emory University, Atlanta, Georgia, USA. [2] Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
6
1] Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. [2] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA. [3] Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, USA.
7
1] Department of Pediatrics, Stanford University, Stanford, California, USA. [2] Department of Bioengineering, Stanford University, Stanford, California, USA.

Abstract

An effective method for direct chemical control over the production of specific proteins would be widely useful. We describe small molecule-assisted shutoff (SMASh), a technique in which proteins are fused to a degron that removes itself in the absence of drug, resulting in the production of an untagged protein. Clinically tested HCV protease inhibitors can then block degron removal, inducing rapid degradation of subsequently synthesized copies of the protein. SMASh allows reversible and dose-dependent shutoff of various proteins in multiple mammalian cell types and in yeast. We also used SMASh to confer drug responsiveness onto an RNA virus for which no licensed inhibitors exist. As SMASh does not require the permanent fusion of a large domain, it should be useful when control over protein production with minimal structural modification is desired. Furthermore, as SMASh involves only a single genetic modification and does not rely on modulating protein-protein interactions, it should be easy to generalize to multiple biological contexts.

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PMID:
26214256
PMCID:
PMC4543534
DOI:
10.1038/nchembio.1869
[Indexed for MEDLINE]
Free PMC Article

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