Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• CREB-binding protein (CBP) is a crucial scaffold protein complex involved in transcription regulation.
• CBP interacts allosterically with ligands like mixed-lineage leukemia (MLL) and c-Myb.
• Understanding allostery in CBP is vital for deciphering gene regulation mechanisms.

Purpose of the Study:

• To investigate the allosteric mechanisms of CBP using computational methods.
• To identify specific regions within the KIX domain responsible for allosteric signal propagation.
• To validate residue-based interaction energy calculations for studying allostery.

Main Methods:

• Conducted molecular dynamics (MD) simulations of the KIX:MLL:c-Myb ternary complex and its components.
• Performed residue-based interaction energy calculations.
• Utilized cross-correlation analysis to analyze protein dynamics.

Main Results:

• MD simulations revealed significant similarities between KIX:MLL and KIX:c-Myb:MLL complexes.
• Two key regions in the KIX backbone were identified: one for ligand binding and another for allosteric signal propagation (L12-G2 loop and α3 helix).
• Residue-based interaction energy calculations effectively detected allosteric signal propagation and ligand interaction sites.

Conclusions:

• The study successfully identified critical regions in CBP's KIX domain involved in allosteric regulation.
• Residue-based interaction energy calculation is a valuable technique for probing allosteric mechanisms in protein complexes.
• These findings enhance our understanding of transcription regulation mediated by CBP.