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A General Chemical Method to Regulate Protein Stability in the Mammalian Central Nervous System

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Author

Summary, in English

The ability to make specific perturbations to biological molecules in a cell or organism is a central experimental strategy in modern research biology. We have developed a general technique in which the stability of a specific protein is regulated by a cell-permeable small molecule. Mutants of the Escherichia coil dihydrofolate reductase (ecDHFR) were engineered to be degraded, and, when this destabilizing domain is fused to a protein of interest, its instability is conferred to the fused protein resulting in rapid degradation of the entire fusion protein. A small-molecule ligand trimethoprim (TMP) stabilizes the destabilizing domain in a rapid, reversible, and dose-dependent manner, and protein levels in the absence of TMP are barely detectable. The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system.

Publishing year

2010

Language

English

Pages

981-988

Publication/Series

Chemistry and Biology

Volume

17

Issue

9

Document type

Journal article

Publisher

Cell Press

Topic

  • Neurosciences

Status

Published

Research group

  • Brain Repair and Imaging in Neural Systems (BRAINS)
  • CNS Gene Therapy

ISBN/ISSN/Other

  • ISSN: 1879-1301