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Signal Propagation Within the MCL-1/BIM Protein Complex


Heckmeier, Philipp J; Ruf, Jeannette; Buhrke, David; Janković, Brankica G; Hamm, Peter (2022). Signal Propagation Within the MCL-1/BIM Protein Complex. Journal of Molecular Biology, 434(17):167499.

Abstract

The protein MCL-1 is a crucial factor in regulating apoptosis, the programmed cell death, and thus plays a major role in numerous cancer types. The allosteric protein MCL-1 is naturally moderated by the BH3-only peptide BIM, which binds at its canonical binding groove. In its isolated form, BIM is disordered but assumes an -helical shape when bound by MCL-1. The underlying binding mechanism (i.e., induced fit vs conformational selection), as well as the time scales of the signal cascade subsequent to binding, are not understood. Here, an artificially photoswitchable variant of the MCL-1/BIM complex was designed and investigated by transient infrared spectroscopy. By destabilizing the -helix of BIM with a covalently linked azobenzene photoswitch, the dynamical response of the whole complex upon an ultrafast photo-perturbation was characterized. While the destabilized and partially unfolded BIM still binds to MCL-1, a step-like cascade of structural rearrangements of both, MCL-1 and BIM was detected, spanning a wide range of time scales from pico- to microseconds. The results indicate that BIM binds according to an induced fit mechanism, while the structural adaptations of MCL-1 may constitute an allosteric signal.

Abstract

The protein MCL-1 is a crucial factor in regulating apoptosis, the programmed cell death, and thus plays a major role in numerous cancer types. The allosteric protein MCL-1 is naturally moderated by the BH3-only peptide BIM, which binds at its canonical binding groove. In its isolated form, BIM is disordered but assumes an -helical shape when bound by MCL-1. The underlying binding mechanism (i.e., induced fit vs conformational selection), as well as the time scales of the signal cascade subsequent to binding, are not understood. Here, an artificially photoswitchable variant of the MCL-1/BIM complex was designed and investigated by transient infrared spectroscopy. By destabilizing the -helix of BIM with a covalently linked azobenzene photoswitch, the dynamical response of the whole complex upon an ultrafast photo-perturbation was characterized. While the destabilized and partially unfolded BIM still binds to MCL-1, a step-like cascade of structural rearrangements of both, MCL-1 and BIM was detected, spanning a wide range of time scales from pico- to microseconds. The results indicate that BIM binds according to an induced fit mechanism, while the structural adaptations of MCL-1 may constitute an allosteric signal.

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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:Life Sciences > Biophysics
Life Sciences > Structural Biology
Life Sciences > Molecular Biology
Uncontrolled Keywords:Molecular Biology, Structural Biology
Language:English
Date:1 September 2022
Deposited On:03 May 2022 09:28
Last Modified:19 Jun 2024 03:43
Publisher:Elsevier
ISSN:0022-2836
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jmb.2022.167499
Project Information:
  • : FunderSNSF
  • : Grant ID200020B_188694
  • : Project TitleUltrafast Vibrational Spectroscopy of Allosteric Proteins (Extension)
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)