Trading off stability for activity
Oeiras, 05.01.10
Frataxin is a mitochondrial protein involved in iron metabolism found to be defective in the neurodegenerative disorder Freidreich’s ataxia. How this protein works in the cell and how it interacts with other proteins is a fundamental question whose answers will contribute to a better understanding of the disease. Using the baker’s yeast protein as a model, researchers from Laboratory of Protein Biochemistry, Folding & Stability and co-workers from University of Wisconsin showed that frataxin’s design favours function over stability. The research is published in the January issue of the Biochemical Journal.
Proteins consist of a chain of amino acids that can fold into different three-dimensional structures and these are determinant for protein’s function and stability. While common sense tells us that stable proteins should be functional, the fact is that making the protein stable as a rock reduces its ability to bind to other molecules.
In frataxin, one particular region rich in negatively charged amino acids - the so called acidic ridge - was thought to be important for function. Researchers confirmed this hyphothesis by engineering changes in this ridge and further showed that the biological function of frataxin is affected as a result of a trade off between function and stability: the modifications decreased the protein’s binding activity because the protein becomes less flexible and more stable towards thermal denaturation (impressively, its thermal stability increases from 40°C to 64°C). This effect is illustrative of a fundamental principle in protein chemistry and contributes to a better understanding of how the amino acid sequence determines protein structure and function.
This project was partly funded by a research grant award from the American National Ataxia Foundation.
Original article
Biochem. J. (2009) Immediate Publication, doi:10.1042/BJ20091612
Iron binding activity in yeast frataxin entails a trade off with stability in the α1/β1 acidic ridge region
