Deciphering the promiscuous interactions between intrinsically disordered transactivation domains and the KIX domain

Area of Science:

• Molecular Biology
• Biophysics
• Protein-protein interactions

Background:

• The CBP KIX domain binds multiple intrinsically disordered transactivation domains (TADs) through distinct sites: the c-Myb site and the MLL site.
• These TADs include c-Myb, pKID, MLL, E2A, and c-Jun, highlighting the promiscuous nature of KIX domain interactions.

Purpose of the Study:

• To computationally investigate the kinetics of various disordered TADs binding to the KIX domain.
• To elucidate the role of long-range electrostatic interactions in modulating these binding events.
• To understand the binding mechanism of multi-motif TADs like FOXO3a and p53 to the KIX domain.

Main Methods:

• Computational biophysical analyses were employed to compare binding kinetics.
• Rate constants for encounter complex formation were analyzed.
• The influence of electrostatic interactions on association rates was assessed.

Main Results:

• Long-range electrostatic interactions critically affect binding rates between TADs and the KIX domain.
• Favorable electrostatics between the MLL site and peptides enhance association rates.
• FOXO3a and p53 TADs bind the KIX domain via a sequential mechanism, involving both MLL and c-Myb sites.

Conclusions:

• Electrostatic steering plays a crucial role in simplifying the binding of multi-motif intrinsically disordered proteins to the KIX domain.
• This study underscores the importance of long-range electrostatics in molecular recognition, especially for promiscuous interactions involving intrinsically disordered proteins.