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


RESULTS
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.


CONCLUSIONS
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.
Grills
Claire
C
School of Applied Mathematics and Theoretical Physics, Queens University Belfast, Belfast, Northern Ireland.
Crawford
Nyree
N
Chacko
Alex
A
Johnston
Patrick G
PG
O'Rourke
Francesca
F
Fennell
Dean A
DA
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045643:DNA Repair Enzymes; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C474007:Bax protein (53-86); D002352:Carrier Proteins; C484586:HRK protein, human; C476254:N4BP2 protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045643:DNA Repair Enzymes