- One activator, Bid.
- Two sensitizers, Bad and Noxa.
- Two effectors, Bax and Bak.
- Three anti-apoptotics, Bcl-2, Bcl-xL, and Mcl-1.
Note that in each of the three models, interactions between Bcl-2 proteins only occur at the mitochondrial membrane. The following are brief descriptions of each model.
direct(). In this model, tBid directly activates both Bax and Bak; the anti-apoptotics bind tBid and the sensitizers (Bad and Noxa) but not Bax and Bak.
indirect(). Bax and Bak are not explicitly activated by tBid, but rather are in an equilibrium between inactive and active states. The anti-apoptotics bind tBid, sensitizers, and Bax and Bak.
embedded(). Combines elements of both direct and indirect: tBid activates Bax and Bak; the anti-apoptotics bind tBid, sensitizers and Bax and Bak. In addition, Bax and Bak are able to auto-activate.
Organization of models into Motifs¶
Because the three models share many aspects, the mechanisms that they share have been written as small “motifs” implemented as subroutines. These are:
The implementation details of these motifs can be seen by examining the source code.
Declare the monomers for the Bcl-2 family proteins, Cyto c, and Smac.
Annotation() declarations embedded in this function associate UniProt identifiers with each protein.
‘bf’ is the site to be used for all binding reactions (with the exception of Bax and Bak, which have additional sites used for oligomerization).
The ‘state’ site denotes various localization and/or activity states of a Monomer, with ‘C’ denoting cytoplasmic localization and ‘M’ mitochondrial localization. Most Bcl-2 proteins have the potential for both cytoplasmic and mitochondrial localization, with the exceptions of Bak and Bcl-2, which are apparently constitutively mitochondrial.
Declare initial conditions for Bcl-2 family proteins, Cyto c, and Smac.
tBid, Bax and BclXL translocate to the mitochondrial membrane.
tBid activates Bax and Bak.
tBid binds and inhibits Bcl2, Mcl1, and Bcl-XL.
The entries given in the bind_table are dissociation constants taken from Certo et al. (see ref). Dissociation constants in Certo et al. were published as nanomolar binding affinities; here they are converted into units of numbers of molecules by multiplying by N_A (Avogadro’s number) and V (a default cell volume, specified in shared.py.
The default forward rate represents diffusion limited association (1e6 Molar^-1 s^-1) and is converted into units of molec^-1 s^-1 by dividing by N_A*V.
Certo, M., Del Gaizo Moore, V., Nishino, M., Wei, G., Korsmeyer, S., Armstrong, S. A., & Letai, A. (2006). Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell, 9(5), 351-365. doi:10.1016/j.ccr.2006.03.027
Binding of Bad and Noxa to Bcl2, Mcl1, and Bcl-XL.
See comments on units for
Binding of Bax and Bak to Bcl2, BclxL, and Mcl1.
Affinities of Bak for Bcl-xL and Mcl-1 are taken from Willis et al.
Preferential affinity of Bax for Bcl-2 and Bcl-xL were taken from Zhai et al. Bax:Bcl2 and Bax:Bcl-xL affinities were given order of magnitude estimates of 10nM.
See comments on units for
Willis, S. N., Chen, L., Dewson, G., Wei, A., Naik, E., Fletcher, J. I., Adams, J. M., et al. (2005). Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes & Development, 19(11), 1294-1305. doi:10.1101/gad.1304105
Zhai, D., Jin, C., Huang, Z., Satterthwait, A. C., & Reed, J. C. (2008). Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family proteins Bcl-B and Mcl-1. The Journal of biological chemistry, 283(15), 9580-9586. doi:10.1074/jbc.M708426200
Pore formation and transport process used by all modules.
Direct and indirect modes of action, occurring at the membrane.
Bax and Bak spontaneously form pores without activation. The “activator” tBid binds all of the anti-apoptotics.
Anti-apoptotics prevent BH3-onlies from activating Bax and Bak.
Bax and Bak require activation to be able to form pores. The anti-apoptotics don’t inhibit activated Bax and Bak; their only role is to bind BH3-onlies.