Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins
A search through hydrophobic chemical space identifies an adamantane tag that targets dehalogenase fusion proteins for degradation, as demonstrated for both cytosolic and transmembrane proteins; and in zebrafish and mice. This molecule provides a new tool to study protein function with precise contr...
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Published in | Nature chemical biology Vol. 7; no. 8; pp. 538 - 543 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
03.07.2011
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | A search through hydrophobic chemical space identifies an adamantane tag that targets dehalogenase fusion proteins for degradation, as demonstrated for both cytosolic and transmembrane proteins; and in zebrafish and mice. This molecule provides a new tool to study protein function with precise control.
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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Bibliography: | Current address: Dept. of Ophthalmology, Indiana University School of Medicine these authors contributed equally to this work |
ISSN: | 1552-4450 1552-4469 |
DOI: | 10.1038/nchembio.597 |