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

Esther Wolf, Cristina Lento, Jinyue Pu, View ORCID ProfileBryan C. Dickinson, View ORCID ProfileDerek J. Wilson
doi: https://doi.org/10.1101/2022.06.10.495660
Esther Wolf
1Department of Chemistry, York University, Toronto, ON, Canada M3J 1P3
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Cristina Lento
1Department of Chemistry, York University, Toronto, ON, Canada M3J 1P3
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Jinyue Pu
2Department of Chemistry, The University of Chicago, 5801 South Ellis Avenue, Chicago, IL, USA
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Bryan C. Dickinson
2Department of Chemistry, The University of Chicago, 5801 South Ellis Avenue, Chicago, IL, USA
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Derek J. Wilson
1Department of Chemistry, York University, Toronto, ON, Canada M3J 1P3
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  • ORCID record for Derek J. Wilson
  • For correspondence: dkwilson@yorku.ca
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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 Statement This 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.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations and Symbols

    Bcl-2
    B-cell lymphoma 2 protein
    BH
    Bcl-2 Homology domain
    ESI-MS
    Electrospray Ionization Mass
    HDX-MS
    Hydrogen-Deuterium Exchange Mass Spectrometry
    IMS
    Ion Mobility Spectrometry
    Mcl-1
    Induced myeloid leukemia cell differentiation protein
    MOMP
    Mitochondrial Outer Membrane Permeabilization
    PDB
    protein data bank
    RMSD
    root mean squared deviation
    tBid
    truncated Bid
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2
    Esther Wolf, Cristina Lento, Jinyue Pu, Bryan C. Dickinson, Derek J. Wilson
    bioRxiv 2022.06.10.495660; doi: https://doi.org/10.1101/2022.06.10.495660
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    Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2
    Esther Wolf, Cristina Lento, Jinyue Pu, Bryan C. Dickinson, Derek J. Wilson
    bioRxiv 2022.06.10.495660; doi: https://doi.org/10.1101/2022.06.10.495660

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