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arXiv · 2211.08934

MCL-1 promiscuity and the structural resilience of its binding partners

Philipp J. Heckmeier·Jeannette Ruf·Brankica G. Janković·Peter Hamm
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Abstract

MCL-1 and its natural inhibitors, the BH3-only proteins PUMA, BIM, and NOXA regulate apoptosis by interacting promiscuously within an entangled binding network. Little is known about the transient processes and dynamic conformational fluctuations that are the basis for the formation and stability of the MCL-1/BH3-only complex. In this study, we designed photoswitchable versions of MCL-1/PUMA and MCL-1/NOXA, and investigated the protein response after an ultrafast photo-perturbation with transient infrared spectroscopy. We observed partial $\alpha$-helical unfolding in all cases, albeit on strongly varying timescales (1.6~ns for PUMA, 9.7~ns for the previously studied BIM, and 85~ns for NOXA). These differences are interpreted as a BH3-only-specific "structural resilience" to defy the perturbation while remaining in MCL-1's binding pocket. Thus, the presented insights could help to better understand the differences between PUMA, BIM, and NOXA, the promiscuity of MCL-1 in general, and the role of the proteins in the apoptotic network.

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Philipp J. Heckmeier, Jeannette Ruf, Brankica G. Janković, Peter Hamm. 2022-11-16. MCL-1 promiscuity and the structural resilience of its binding partners. https://doi.org/10.1063/5.0137239

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