Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins
Open accessAbstract
The ability to regulate any protein of interest in living systems with small molecules remains a challenge. We hypothesized that appending a hydrophobic moiety to the surface of a protein would mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. We designed and synthesized bifunctional small molecules to bind a bacterial dehalogenase (the HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with an adamantyl moiety induced the degradation of cytosolic, isoprenylated and transmembrane HaloTag fusion proteins in cell culture. We demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting Hras1(G12V)-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small-molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
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Nabet and colleagues developed the dTag system that uses PROTACs composed of a CRBN or VHL ligand, a linker and an AP1867 derivative.
“In addition, Nabet and colleagues200,201 have developed the dTag system that uses PROTACs composed of a CRBN or VHL ligand, a linker and an AP1867 derivative.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [201]
AP1867-derivative PROTACs can mediate selective degradation of heterologous FKBP12F36V-tagged proteins, enforcing rapid and potent depletion in vitro and in vivo.
“Accordingly, AP1867-derivative PROTACs can mediate the selective degradation of heterologous FKBP12F36V-tagged proteins, enforcing rapid and potent depletion in vitro and in vivo200,201.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [201]
HALO-tagged fusions of transmembrane proteins with differing amounts of membrane spanning helices could be degraded by the HyT system.
“Remarkably, HALO-tagged fusions of transmembrane proteins with differing amounts of membrane spanning helices could be degraded by this system as well [56].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [56]
Molecular chaperones Hsp70 and Hsp90 can recruit the co-chaperone E3 ligase CHIP, leading to ubiquitination and degradation of chaperone-bound client proteins.
“However, molecular chaperones Hsp70 and Hsp90 can also recruit the co-chaperone E3 ligase CHIP (C-terminus of Hsp70 interacting protein), which leads to ubiquitination and degradation of the chaperone-bound client proteins [56–59].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [56]
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“Hydrophobic tagging strategies (Hyts) exploit the cell’s quality control machinery to trigger degradation (Neklesa et al. 2011) (see table 1 and Figure 2B).”
- Authors
- Neklesa, T. K., Tae, H. S., Schneekloth, A. R., Stulberg, M. J., Corson, T. W., Sundberg, T. B., Raina, K., Holley, S. A., & Crews, C. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crews, Craig M
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2011-07-03
- Volume
- 7
- Issue
- 8
- Pages
- 538-543
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3139752
- OpenAlex
- W1982166691
- Cited by
- 429
- References
- 43
- Citations by year
- 2026: 33 · 2025: 39 · 2024: 40 · 2023: 43 · 2022: 37 · 2021: 46 · 2020: 43 · 2019: 30 · 2018: 23 · 2017: 24 · 2016: 15 · 2015: 15 · 2014: 15 · 2013: 11 · 2012: 13
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI084140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- HaloTag, protein degradation, dehalogenase, adamantane, bifunctional small molecules, proteasomal degradation, transmembrane proteins, protein quality control, HRAS G12V, tumor progression, zebrafish, drug target validation
- MeSH terms
- Animals, Cell Line, Fluorescent Dyes, Humans, Luminescent Proteins, Recombinant Proteins, Sensitivity and Specificity, Staining and Labeling, Zebrafish, Biosensing Techniques, Molecular Structure, Mice, Hydrophobic and Hydrophilic Interactions
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