The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core
Autor: | Thomas E. Wales, John R. Engen, Noah B. Bloch, Hannah R. Levy, Michelle S. Prew, Loren D. Walensky |
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Rok vydání: | 2021 |
Předmět: |
Models
Molecular Conformational change Protein Conformation Science Cell General Physics and Astronomy Apoptosis Mitochondrion Article General Biochemistry Genetics and Molecular Biology Cytosol medicine Animals Humans Amino Acids Cells Cultured bcl-2-Associated X Protein Mice Knockout Binding Sites Multidisciplinary Mass spectrometry Chemistry Protein core General Chemistry Oncogene proteins Mitochondria Cell biology medicine.anatomical_structure Mutation Helix Conformational stability Protein Multimerization Structural biology Protein Binding Signal Transduction |
Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
ISSN: | 2041-1723 |
Popis: | BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation. The pro-apoptotic BAX protein is a monomer under homeostatic conditions and, in response to stress, transforms into oligomers that induce apoptosis. Here, the authors characterize structural features of BAX that individually stabilize the monomer while collectively contributing to oligomerization. |
Databáze: | OpenAIRE |
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