Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains.

Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains. Research Abstract Details 

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Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains. Abstract Text:

INTRODUCTION: The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models have been proposed. In one, BAK requires so-called activating BH3 only proteins (aBH3) to initiate its conformation change. In the other, displacement from inhibitory pro-survival BCL-2 proteins (PBPs) and monomerization of BAK by PBP selective dissociator BH3-only proteins (dBH3) is sufficient. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the kinetic implications of these conflicting but highly evidence-based models, we have conducted a deterministic, dynamical systems analysis to explore the kinetics underlying the first step of BAK activation, as a non-linear reaction system. We show that dBH3 induced BAK activation is efficient, even in the absence of aBH3s, provided constitutive interaction of PBPs with open conformation BAK occurs in an adenoviral E1B 19K-like manner. The pattern of PBP expression robustly predicts the efficacy of dBH3s. CONCLUSION: Our findings accommodate the prevailing BAK activation models as potentially coexisting mechanisms capable of initiating BAK activation, and supports a model based approach for predicting resistance to therapeutically relevant small molecule BH3 mimetics.

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Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: PLoS ONE

VOLUME: 3

Page Numbers: e3038

Journal Abbreviation: PLoS ONE

ISSN: 1932-6203

DAY: 22

MONTH: 08

YEAR: 2008

Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains. Information

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LANGUAGE: eng

NlmUniqueID: 101285081

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Grant and Affiliation Information for Dynamical systems analysis of mitochondrial BAK activation kinetics predicts resistance to BH3 domains.

AFFILIATION: School of Applied Mathematics and Theoretical Physics, Queens University Belfast, Belfast, Northern Ireland.

Country: United States

AGENCY: United Kingdom Cancer Res

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MEDLINETA: PLoS ONE

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