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Nat Commun. 2017 Jul 13;8(1):73. doi: 10.1038/s41467-017-00086-6.

Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation.

Author information

1
Max Planck Institute for Intelligent Systems, Heisenbergstr. 3, 70569, Stuttgart, Germany.
2
German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
3
Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany.
4
ZEMOS, Ruhr-University Bochum, Universitätsstr. 150, 44801, Bochum, Germany.
5
University of Konstanz, Applied Bioinformatics, Universitaetsstr. 10, 78457, Konstanz, Germany.
6
Max Planck Institute for Intelligent Systems, Heisenbergstr. 3, 70569, Stuttgart, Germany. ana.garcia@uni-tuebingen.de.
7
German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. ana.garcia@uni-tuebingen.de.
8
Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany. ana.garcia@uni-tuebingen.de.

Abstract

The Bcl-2 proteins form a complex interaction network that controls mitochondrial permeabilization and apoptosis. The relative importance of different Bcl-2 complexes and their spatio-temporal regulation is debated. Using fluorescence cross-correlation spectroscopy to quantify the interactions within a minimal Bcl-2 network, comprised by cBid, Bax, and Bcl-xL, we show that membrane insertion drastically alters the pattern of Bcl-2 complexes, and that the C-terminal helix of Bcl-xL determines its binding preferences. At physiological temperature, Bax can spontaneously activate in a self-amplifying process. Strikingly, Bax also recruits Bcl-xL to membranes, which is sufficient to retrotranslocate Bax back into solution to secure membrane integrity. Our study disentangles the hierarchy of Bcl-2 complex formation in relation to their environment: Bcl-xL association with cBid occurs in solution and in membranes, where the complex is stabilized, whereas Bcl-xL binding to Bax occurs only in membranes and with lower affinity than to cBid, leading instead to Bax retrotranslocation.The permeabilization of the mitochondrial outer membrane to induce apoptosis is regulated by complex interactions between Bcl-2 family members. Here the authors develop a quantitative interactome of a membrane Bcl-2 network and identify a hierarchy of protein complexes in apoptosis induction.

PMID:
28706229
PMCID:
PMC5509671
DOI:
10.1038/s41467-017-00086-6
[Indexed for MEDLINE]
Free PMC Article

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