Hot spots for allosteric regulation on protein surfaces

Area of Science:

• Protein structure and function
• Biochemistry
• Evolutionary biology

Background:

• Proteins possess a general architecture based on sparse networks of physically contiguous and coevolving amino acids, known as sectors.
• These sectors link active sites to surface sites, influencing protein structure and function.
• Sectors are spatially organized, suggesting a role in protein regulation.

Purpose of the Study:

• To investigate the relationship between protein sectors and enzyme catalysis.
• To determine if sector-connected surface sites are preferential locations for allosteric control.
• To elucidate the role of sectors in protein evolution and regulation.

Main Methods:

• Utilized dihydrofolate reductase as a model system.
• Correlated sector networks with millisecond conformational fluctuations during enzyme catalysis.
• Analyzed the statistical preference of sector-connected surface sites for allosteric control emergence in vivo.

Main Results:

• The protein sector in dihydrofolate reductase strongly correlated with residues exhibiting millisecond conformational fluctuations linked to catalysis.
• Sector-connected surface sites were found to be statistically preferred locations for the in vivo emergence of allosteric control.
• Demonstrated that sectors act as an evolutionarily conserved wiring mechanism.

Conclusions:

• Sectors facilitate rapid conformational control of protein function through perturbations at specific surface positions.
• Sectors represent a conserved mechanism enabling intermolecular communication and regulation in proteins.
• The findings suggest sectors are crucial for the evolution of protein allostery and function.