Molecular gymnastics: serpin structure, folding and misfolding

Area of Science:

• Biochemistry
• Structural Biology
• Protein Dynamics

Background:

• Serpins are crucial proteinase inhibitors.
• Their native state is a metastable intermediate on the folding pathway.
• Protease interaction triggers a conformational change to a more stable state.

Purpose of the Study:

• To elucidate how serpins' folding dynamics and metastability contribute to protease inhibition.
• To understand the evolutionary advantage of using protein folding processes for function.

Main Methods:

• Analysis of serpin native states and folding pathways.
• Investigating the mechanism of protease-serpin interaction.
• Studying the dynamics of serpin conformational changes.

Main Results:

• The native serpin state is a long-lived metastable intermediate.
• Protease binding initiates a rapid folding into a stable conformation.
• Alternative unproductive folding pathways lead to inactive serpin conformations.
• Evolution exploits protein folding dynamics for serpin function.

Conclusions:

• Serpin function is intrinsically linked to their folding pathway and metastability.
• Metastability, while enabling function, elevates the risk of protein misfolding.
• Understanding serpin dynamics offers insights into protein folding and evolution.