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

Heckmeier, Philipp J; Ruf, Jeannette; Janković, Brankica G; Hamm, Peter (2023). MCL-1 promiscuity and the structural resilience of its binding partners. Journal of Chemical Physics, 158(9):095101.

Abstract

The allosteric protein 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 α-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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > General Physics and Astronomy
Physical Sciences > Physical and Theoretical Chemistry
Uncontrolled Keywords:Physical and Theoretical Chemistry, General Physics and Astronomy
Language:English
Date:7 March 2023
Deposited On:18 Feb 2024 15:31
Last Modified:30 Jan 2025 02:38
Publisher:American Institute of Physics
ISSN:0021-9606
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1063/5.0137239
PubMed ID:36889945
Project Information:
  • Funder: SNF
  • Grant ID: 200020B_188694/1
  • Project Title:
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  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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