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Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study
Published on: July 27, 2016
Analysis of type 1 ryanodine receptor-12 kDa FK506-binding protein interaction
J J Mackrill1, S O'Driscoll, F A Lai
1Department of Biochemistry, University College Cork, National University of Ireland, Cork, Ireland. stbi8042@ucc.ie
Biochemical and Biophysical Research Communications
|July 5, 2001
Summary
The FKBP12-RyR1 complex is stable under various physiological conditions. Ascomycin, an FK506 analogue, is the first identified drug to disrupt this crucial protein interaction.
Area of Science:
- Molecular Biology
- Biochemistry
- Pharmacology
Background:
- The interaction between FKBP12 (12 kDa FK506 binding protein) and RyR1 (type 1 ryanodine receptor) is critical for cellular function.
- While macrolide immunosuppressants are known to dissociate this complex, the effects of other solutes and drugs remain largely unquantified.
- Understanding factors affecting FKBP12-RyR1 binding is essential for drug development and understanding RyR1 channelopathies.
Purpose of the Study:
- To quantitate the influence of various solutes and drugs on the binding affinity between solubilized RyR1 and an FKBP12-glutathione-S-transferase fusion protein.
- To identify novel compounds capable of disrupting the FKBP12-RyR1 complex.
- To assess the stability of the FKBP12-RyR1 complex under varying physiological conditions.
Main Methods:
- Development and application of a novel assay to measure the binding between solubilized RyR1 and FKBP12-glutathione-S-transferase fusion protein.
- Systematic analysis of the complex's stability under different temperatures, pH levels, cation concentrations, and in the presence of endogenous solutes.
- Screening of various drugs, including FK506 analogues, for their ability to dissociate the FKBP12-RyR1 complex.
Main Results:
- The association between FKBP12 and RyR1 is robust and shows significant stability across physiological ranges of temperature, pH, cations, and endogenous solutes.
- No substantial alteration in FKBP12-RyR1 binding was observed with changes in these common physiological parameters.
- Ascomycin, an analogue of FK506, was identified as a novel drug capable of disrupting the FKBP12-RyR1 complex.
Conclusions:
- The FKBP12-RyR1 complex exhibits remarkable stability under physiological conditions, suggesting a strong intrinsic interaction.
- Ascomycin represents a new class of compounds, distinct from known macrolide immunosuppressants, that can dissociate the FKBP12-RyR1 complex.
- These findings provide a foundation for further investigation into the structural and functional implications of FKBP12-RyR1 interactions and their modulation by pharmacological agents.
