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Regulation of protein function by native metastability
1National Creative Research Initiative Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Taejon 305-333, Korea.
Summary
Native metastability in proteins like serpins is crucial for function. Filling cavities in alpha(1)-antitrypsin increased stability but decreased inhibitory activity, suggesting metastability is a design for protein function regulation.
Area of Science:
- Protein structure and function
- Biochemistry
- Molecular biology
Background:
- Native proteins are typically in their most stable state.
- Inhibitory serpins and viral fusion proteins exist in a metastable native state, essential for their biological roles.
- Structural defects like cavities contribute to this metastability.
Purpose of the Study:
- To investigate the functional consequences of altering native metastability in alpha(1)-antitrypsin, a prototype serpin.
- To elucidate the mechanism by which structural defects regulate protein function.
Main Methods:
- Characterization of cavity-filling mutations in alpha(1)-antitrypsin.
- Analysis of conformational stability in relation to side-chain volume.
- Correlation of stability with inhibitory activity and conformational switch rates.
Main Results:
- Conformational stability increased linearly with the van der Waals volume of introduced side chains.
- Increased conformational stability was directly correlated with decreased inhibitory activity.
- Activity loss correlated with a reduced rate of conformational switching upon protease binding.
Conclusions:
- Native protein metastability is a deliberate structural design feature.
- This metastability plays a critical role in regulating protein function, particularly inhibitory activity in serpins.
- Altering structural defects like cavities impacts protein dynamics and function.