Bcl-2 family controls mitochondrial outer membrane permeabilization by performing non-trivial pattern recognition

TL;DR

This paper uses mathematical modeling and computational simulation to analyze how the Bcl-2 family proteins regulate mitochondrial membrane permeabilization, revealing non-linear, bistable, and switch-like responses based on specific protein interactions.

Contribution

It introduces a novel computational approach to understand Bcl-2 family regulation, highlighting the role of specific interactions in emergent switch-like behavior.

Findings

Bcl-2 family interactions produce bistability and switch-like responses.

Principal component analysis classifies inputs into two distinct response classes.

Specific organization of protein interactions is essential for observed behavior.

Abstract

Interactions between individual members of the B-cell lymphoma 2 (Bcl-2) family of proteins form a regulatory network governing mitochondrial outer membrane permeabilization (MOMP). Bcl-2 family initiated MOMP causes release of the inter-membrane pro-apoptotic proteins to cytosol and creates a cytosolic environment suitable for the executionary phase of apoptosis. Using mathematical modeling and computational simulation, we have analyzed the response of this regulatory network caused by the up-/downregulation of each individual member of the Bcl-2 family. As a result, a non-linear stimulus-response emerged, the characteristics of which are associated with bistability and switch-like behavior. Using the principal component analysis (PCA) we have shown that the Bcl-2 family classifies the random combinations of inputs into two distinct classes, and responds to these by one of the two qualitatively distinct outputs. As we showed, the emergence of this behavior requires specific organization of the interactions between particular Bcl-2 proteins.