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Stanford University

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Nat. Chem. Biol., Published online 27 July 2015 | doi:10.1038/nchembio.1869 Tunable and reversible drug control of protein production via a self-excising degron

Abstract

Hokyung K Chung¹, Conor L Jacobs¹, Yunwen Huo², Jin Yang³, Stefanie A Krumm⁴, Richard K Plemper^4,5, Roger Y Tsien^3,6,7 & Michael Z Lin^2,8*

¹Department of Biology, Stanford University, Stanford, California, USA. ²Department of Pediatrics, Stanford University, Stanford, California, USA. ³Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. ⁴Department of Pediatrics, Emory University, Atlanta, Georgia, USA. ⁵Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA. ⁶Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA. ⁷Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, USA. ⁸Department of Bioengineering, Stanford University, Stanford, California, USA.

^*Correspondence to : Michael Z Lin

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.

논문정보

형식Research article
게재일2015년 07월 (BRIC 등록일 2015-09-18)
연구진국외 연구진
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