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The dTAG system for immediate and target-specific protein degradation

Nature chemical biology, 2018-05, Vol.14 (5), p.431-441 [Peer Reviewed Journal]

Copyright Nature Publishing Group May 2018 ;ISSN: 1552-4450 ;EISSN: 1552-4469 ;DOI: 10.1038/s41589-018-0021-8 ;PMID: 29581585

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Title:
The dTAG system for immediate and target-specific protein degradation
Author: Nabet, Behnam ; Roberts, Justin M ; Buckley, Dennis L ; Paulk, Joshiawa ; Dastjerdi, Shiva ; Yang, Annan ; Leggett, Alan L ; Erb, Michael A ; Lawlor, Matthew A ; Souza, Amanda ; Scott, Thomas G ; Vittori, Sarah ; Perry, Jennifer A ; Qi, Jun ; Winter, Georg E ; Wong, Kwok-Kin ; Gray, Nathanael S ; Bradner, James E
Subjects: Abundance ; Alleles ; Animals ; Biodegradation ; Cell Cycle Proteins ; Cell Proliferation ; Complexity ; CRISPR ; CRISPR-Cas Systems ; Cytoplasm - metabolism ; Degradation ; Dimerization ; Drug discovery ; Gene Knock-In Techniques ; HEK293 Cells ; Homeostasis ; Humans ; In vivo methods and tests ; Ligands ; Mice ; Mutation ; NIH 3T3 Cells ; Nuclear Proteins - chemistry ; Nuclear Proteins - genetics ; Protein Binding ; Protein Domains ; Proteins ; Proteolysis ; Proteomics ; Proto-Oncogene Proteins p21(ras) - genetics ; Signal Transduction ; Signaling ; Tacrolimus Binding Protein 1A - chemistry ; Transcription Factors - genetics ; Transgenes
Is Part Of: Nature chemical biology, 2018-05, Vol.14 (5), p.431-441
Description: Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12 with expression of FKBP12 in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1552-4450
EISSN: 1552-4469
DOI: 10.1038/s41589-018-0021-8
PMID: 29581585
Source: MEDLINE
ProQuest Central

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The dTAG system for immediate and target-specific protein degradation

Copyright Nature Publishing Group May 2018 ;ISSN: 1552-4450 ;EISSN: 1552-4469 ;DOI: 10.1038/s41589-018-0021-8 ;PMID: 29581585

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