Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2

Area of Science:

• Biophysics
• Molecular Biology
• Computational Biology

Background:

• Intrinsically disordered protein regions (IDPRs) play critical roles in cellular regulation.
• The pathogenic impact and compensatory mechanisms of mutations in IDPRs are poorly understood.
• BTG2 protein, a cell cycle regulator, contains a disordered C-terminal tail implicated in disease.

Purpose of the Study:

• To investigate the compensatory mechanisms of single nucleotide variants in the disordered C-terminal tail of BTG2.
• To elucidate the long-distance dynamic coupling between the disordered tail and the structured domain of BTG2.
• To understand how mutations in IDPRs affect protein function and how compensatory mutations rescue function.

Main Methods:

• Molecular dynamics (MD) simulations.
• Time-dependent linear response (TDLR) theory.
• Analysis of allosteric regulation and dynamic coupling in proteins.

Main Results:

• Specific mutations in the disordered tail can counteract the effects of a disease-associated mutation (V141M).
• The disordered tail allosterically regulates critical binding sites, and its weakening contributes to disease.
• Compensatory mutations restore interactions, exerting long-distance dynamic control to rescue protein function.

Conclusions:

• Disordered protein regions can exert allosteric control over distant functional sites.
• Compensatory mutations can rescue protein function through a secondhand allosteric mechanism.
• This study provides a framework for understanding IDPR-related diseases and identifying therapeutic targets.