Computational study of the mechanism of Bcl-2 apoptotic switch

TL;DR

This study uses computational modeling to analyze the Bcl-2 apoptotic switch, revealing that stimulus-response ultrasensitivity is primarily an emergent property of the direct activation mechanism, with implications for understanding apoptosis regulation.

Contribution

The paper develops a general model encompassing both hypotheses and demonstrates that ultrasensitivity arises mainly from the direct activation pathway, challenging the indirect activation model.

Findings

Ultrasensitivity is negatively related to spontaneous effector activation.

Effector activation by activators is necessary for ultrasensitivity.

The direct activation model better explains Bcl-2 switch behavior.

Abstract

Programmed cell death - apoptosis is one of the most studied biological phenomenon of recent years. Apoptotic regulatory network contains several significant control points, including probably the most important one - Bcl--2 apoptotic switch. There are two proposed hypotheses regarding its internal working - the indirect activation and direct activation models. Since these hypotheses form extreme poles of full continuum of intermediate models, we have constructed more general model with these two models as extreme cases. By studying relationship between model parameters and steady-state response ultrasensitivity we have found optimal interaction pattern which reproduces behavior of Bcl-2 apoptotic switch. Our results show, that stimulus-response ultrasensitivity is negatively related to spontaneous activation of Bcl-2 effectors - subgroup of Bcl-2 proteins. We found that ultrasensitivity requires effector's activation, mediated by another subgroup of Bcl-2 proteins - activators. We have shown that the auto-activation of effectors forms ultrasensitivity enhancing feedback loop, only if mediated by monomers, but not by oligomers. Robustness analysis revealed that interaction pattern proposed by direct activation hypothesis is able to conserve stimulus-response dependence and preserve ultrasensitivity despite large changes of its internal parameters. This ability is strongly reduced as for the intermediate to indirect side of the models. Computer simulation of the more general model presented here suggest, that stimulus-response ultrasensitivity is an emergent property of the direct activation model, that cannot originate within model of indirect activation. Introduction of indirect-model-specific interactions does not provide better explanation of Bcl-2 functioning compared to direct model.