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bioRxiv · 10.1101/2022.06.10.495660

Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2

Wolf, E. Z.·Lento, C.·Pu, J.·Dickinson, B. C.·Wilson, D. J.
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Abstract

The structurally conserved B-cell Lymphoma 2 (Bcl-2) family of proteins function to promote or inhibit apoptosis through an exceedingly complex web of specific, intrafamilial protein-protein interactions. The critical role of these proteins in lymphomas and other cancers has motivated a widespread interest in understanding the molecular mechanisms that drive specificity in Bcl-2 family interactions. However, the substantial structural similarity amongst Bcl-2 homologues has made it difficult to rationalize the highly specific (and often divergent) binding behavior exhibited by these proteins using conventional structural arguments. In this work, we use millisecond hydrogen deuterium exchange mass spectrometry to explore shifts in conformational dynamics associated with binding partner engagement in Bcl-2 family proteins Bcl-2 and Mcl-1. Using this approach, we reveal that, specifically for Mcl-1, binding specificity arises largely from protein-specific dynamic modes that are accessed in the unbound state. This work has implications for exploring the evolution of internally regulated biological systems composed of structurally similar proteins, and for the development of drugs targeting Bcl-2 family proteins for promotion of apoptosis in cancer. General Interest StatementThis work reveals how a group of proteins, which are highly similar in structure, can form a complex web of highly specific protein-protein interactions that drive programmed cell death (apoptosis) in cancer.

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Wolf, E. Z., Lento, C., Pu, J., Dickinson, B. C., Wilson, D. J.. 2022-06-10. Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2. https://doi.org/10.1101/2022.06.10.495660

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