A Rapid, Reversible, and Tunable Method to Regulate Protein Function in Living Cells Using Synthetic Small Molecules
Open accessAbstract
Rapid and reversible methods for perturbing the function of specific proteins are desirable tools for probing complex biological systems. We have developed a general technique to regulate the stability of specific proteins in mammalian cells using cell-permeable, synthetic molecules. We engineered mutants of the human FKBP12 protein that are rapidly and constitutively degraded when expressed in mammalian cells, and this instability is conferred to other proteins fused to these destabilizing domains. Addition of a synthetic ligand that binds to the destabilizing domains shields them from degradation, allowing fused proteins to perform their cellular functions. Genetic fusion of the destabilizing domain to a gene of interest ensures specificity, and the attendant small-molecule control confers speed, reversibility, and dose-dependence to this method. This general strategy for regulating protein stability should enable conditional perturbation of specific proteins with unprecedented control in a variety of experimental settings.
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Shld1-dependent stability of FKBP12 mutant fusion proteins was demonstrated in various cell lines, including those derived from humans.
“This Shld1-dependent stability was demonstrated in various cell lines, including those derived from humans [23]”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [23]
The Shld1 system requires chronic treatment with the Shld1 ligand to rescue POI levels.
“While this “drug-on” approach is reversible and tuneable, it requires chronic treatment with the Shld1 ligand to rescue the POI levels [23].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [23]
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- Authors
- Banaszynski, L. A., Chen, L.-C., Maynard-Smith, L. A., Ooi, A. G. L., & Wandless, T. J.
- Affiliations
- Stanford University (US)
- Corresponding author
- Wandless, Thomas J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 126
- Issue
- 5
- Pages
- 995-1004
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3290523
- OpenAlex
- W2124833370
- Cited by
- 902
- References
- 45
- Citations by year
- 2026: 45 · 2025: 39 · 2024: 50 · 2023: 59 · 2022: 56 · 2021: 58 · 2020: 54 · 2019: 57 · 2018: 45 · 2017: 52 · 2016: 50 · 2015: 53 · 2014: 52 · 2013: 45 · 2012: 53
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2511 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM068589, R01GM073046, GM068589, GM073046)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- FKBP12, synthetic small molecules, conditional gene expression, ligand binding, mammalian cells
- MeSH terms
- Animals, Gene Expression Regulation, Ligands, Luminescent Proteins, Morpholines, Mutation, Phenotype, Protein Binding, Recombinant Fusion Proteins, Transfection, Protein Structure, Tertiary, Tacrolimus Binding Proteins, Tacrolimus Binding Protein 1A, NIH 3T3 Cells, Proteasome Endopeptidase Complex, Mice
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