Disorder driven allosteric control of protein activity

Area of Science:

• Biophysics
• Structural Biology
• Enzymology

Background:

• Protein allostery is a key regulatory mechanism.
• Order-disorder transitions are increasingly recognized as crucial for allosteric regulation.
• Understanding the interplay between structure and dynamics is vital for protein function.

Purpose of the Study:

• To investigate allosteric mechanisms mediated by structural disorder.
• To apply the structure-based statistical mechanical model of allostery (SBSMMA) to study protein regulation.
• To explore how order-disorder transitions influence protein activity.

Main Methods:

• Utilized the previously developed structure-based statistical mechanical model of allostery (SBSMMA).
• Applied SBSMMA to analyze allosteric communication in specific protein systems.
• Investigated the effects of introducing structural order or disorder in esterases.

Main Results:

• SBSMMA successfully explained the energetics and causality of allosteric communication in BirA biotin repressor dimerization, sortase A activation, and Rac1 GTPase inhibition.
• Modulating structural order/disorder in esterases allowed for tunable allosteric control of the catalytic triad.
• Demonstrated the role of the order-disorder continuum in protein activity modulation.

Conclusions:

• Structural disorder plays a significant role in mediating protein allostery.
• The SBSMMA is a powerful tool for dissecting allosteric mechanisms involving structural dynamics.
• The order-disorder continuum provides a framework for developing tunable allosteric control strategies to modulate protein activity.