Revealing Dynamics-Mediated Effects of Pathogenic Missense Mutations on Menin Protein Function

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Understanding how disease-causing missense mutations (DCMMs) impact protein function is crucial.
• Protein dynamics is increasingly recognized as a key regulator of protein function, yet its role in DCMMs is not fully understood.

Purpose of the Study:

• To investigate the effects of DCMMs on the dynamics of the Menin protein and its interaction with a JunD peptide.
• To elucidate the mechanisms by which DCMMs affect protein-protein interactions, considering both stability and dynamics.

Main Methods:

• Molecular dynamics (MD) simulations were performed on 24 clinically confirmed DCMMs in Menin.
• Rosetta conformation energy calculations and multireplica umbrella sampling were used to assess stability and binding affinities.
• Allosteric analysis was employed to identify the underlying mechanisms of disrupted interactions.

Main Results:

• DCMMs did not necessarily destabilize Menin but induced similar dynamic changes across different mutations.
• DCMMs reduced the binding affinity between Menin and JunD by disrupting the normal dissociation pathway.
• Allosteric analysis revealed that DCMMs uniformly disturbed the coupling between Menin residue E179 and the binding pocket.

Conclusions:

• DCMMs affect Menin-JunD interactions primarily by altering protein dynamics, with allostery playing a significant role.
• The findings emphasize the necessity of incorporating protein dynamics into structure-function frameworks to comprehensively understand the impact of DCMMs.
• Targeting allosteric pathways could offer new therapeutic strategies for diseases associated with Menin dysfunction.