On the Relationship Between Protein Stability, Thermostability, and Allosteric Signaling

Area of Science:

• Protein biophysics
• Structural biology
• Systems biology

Background:

• Protein thermodynamic stability and functional regulation are explained by the energy landscape framework.
• Stability involves a native conformational ensemble, while function relies on transitions between states.
• Allosteric regulation is driven by dynamics and conformational changes.

Purpose of the Study:

• Investigate the relationship between protein structural stability and dynamics-driven allosteric regulation.
• Identify general proteomic trends and specific determinants of protein stability.
• Explore how stability and thermal adaptation influence protein structure and allosteric signaling.

Main Methods:

• Analysis of general proteomic trends.
• Investigation of fold/function-specific stability determinants.
• Utilized a sequence-dependent model of allostery implemented in the AlloSigMA 3 web-server.
• Studied inorganic pyrophosphatase, β-glucosidase, CheY, and adenylate kinase from various organisms.
• Examined allosteric effects of mutations on protein fitness and bacterial growth rates.

Main Results:

• Demonstrated an intricate relationship between protein stability and allosteric regulation.
• Showed that stability and thermal adaptation shape protein structure.
• Identified sequence-structure determinants controlling allosteric signaling.
• Allosteric mutation effects in adenylate kinase correlated with observed changes in bacterial growth rates.
• Observed epistasis, leading to non-additive fitness changes unexplained by stability alone.

Conclusions:

• Protein stability and allosteric regulation are fundamentally interconnected.
• Structural platform is shaped by stability requirements and thermal adaptation.
• Allosteric signaling and regulation are controlled by sequence-structure determinants.
• Epistasis plays a significant role in the effects of mutations on fitness.
• The AlloSigMA 3 web-server provides tools for further investigation of stability-signaling relationships.