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bioRxiv · 10.1101/2024.12.22.630010

Molecular mechanisms of dynamics-mediated effects of pathogenic missense mutations on Menin protein function

Zhang, Q.·Wang, H.·Chen, X.·Li, W.·Peng, J.·Zhang, M.·Sun, B.
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Abstract

Understanding how disease-causing missense mutations (DCMMs) affect protein function is fundamental. The traditional structure-function paradigm for proteins has evolved into a structure-dynamics-function model, as dynamics is increasingly recognized as a key regulator of protein function. Consequently, it is essential to incorporate dynamics into the once heavily emphasized structure-function framework to explain the effects of DCMMs. Although research in this area is emerging, evidence supporting a definitive role of dynamics in mediating DCMM effects on protein function remains limited. In this study, we used Menin--a mutation-prone scaffold protein involved in various pathologies--as a model system to explore how DCMMs affect Menins function. By performing molecular dynamics (MD) simulations on 24 clinically confirmed DCMMs, we showed that DCMMs do not necessarily destabilize protein stability. Instead, they induce similar dynamic changes in the protein. The consequences of DCMMs on Menins function were further assessed through umbrella sampling of the Menin-JunD protein protein interaction (PPI). We found that DCMMs attenuate this interaction and disrupt a highly conserved JunD dissociation pathway in wild-type (WT) Menin. The underlying mechanism was revealed through allosteric analysis, which showed that, despite being located far from the JunD binding site, DCMMs uniformly disturbed the coupling between residue E179 and the binding pocket. Additionally, forced maintenance of E197-pocket coupling restored the impaired Menin-JunD PPI in DCMMs. Together, these data demonstrate that DCMMs alter Menins function through dynamics, with allostery playing a crucial role. This study further supports the incorporation of dynamics into the traditional "structure-function" diagram to better explain the effects of DCMMs.

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Zhang, Q., Wang, H., Chen, X., Li, W., Peng, J., Zhang, M., Sun, B.. 2024-12-25. Molecular mechanisms of dynamics-mediated effects of pathogenic missense mutations on Menin protein function. https://doi.org/10.1101/2024.12.22.630010

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