albeck_modules.py

Overview

PySB implementations of the extrinsic apoptosis reaction model version 1.0 (EARM 1.0) originally published in [Albeck2008].

This file contains functions that implement the extrinsic pathway in three modules:

• Receptor ligation to Bid cleavage (rec_to_bid())
• Mitochondrial Outer Membrane Permeabilization (MOMP, see below)
• Pore transport to effector caspase activation and PARP cleavage (pore_to_parp()).

For the (MOMP) segment there are five variants, which correspond to the five models described in Figure 11 of [Albeck2008]:

• “Minimal Model” (Figure 11b, albeck_11b())
• “Model B + Bax multimerization” (Figure 11c, albeck_11c())
• “Model C + mitochondrial transport” (Figure 11d, albeck_11d())
• “Current model” (Figure 11e, albeck_11e())
• “Current model + cooperativity” (Figure 11f, albeck_11f())

Functions

earm.albeck_modules.ligand_to_c8_monomers()

Declares ligand, receptor, DISC, Flip, Bar and Caspase 8.

‘bf’ is the site to be used for all binding reactions.

The ‘state’ site denotes various localization and/or activity states of a Monomer, with ‘C’ denoting cytoplasmic localization and ‘M’ mitochondrial localization.

earm.albeck_modules.momp_monomers()

Declare the monomers used in the Albeck MOMP modules.

earm.albeck_modules.apaf1_to_parp_monomers()

Declares CytochromeC, Smac, Apaf-1, the Apoptosome, Caspases 3, 6, 9, XIAP and PARP.

The package variable ‘bf’ specifies the name of the site to be used for all binding reactions.

The ‘state’ site denotes various localization and/or activity states of a Monomer, with ‘C’ denoting cytoplasmic localization and ‘M’ mitochondrial localization.

earm.albeck_modules.all_monomers()

Shorthand for calling ligand_to_c8, momp, and apaf1_to_parp macros.

Internally calls the macros ligand_to_c8_monomers(), momp_monomers(), and apaf1_to_parp_monomers() to instantiate the monomers for each portion of the pathway.

earm.albeck_modules.rec_to_bid()

Defines the interactions from ligand (e.g. TRAIL) binding to Bid activation as per EARM 1.0.

Uses L, R, DISC, flip, C8, BAR, and Bid monomers and their associated parameters to generate the rules that describe Ligand/Receptor binding, DISC formation, Caspase-8 activation and inhibition by flip and BAR as originally specified in EARM 1.0.

Declares initial conditions for ligand, receptor, Flip, C8, and Bar.

earm.albeck_modules.pore_to_parp()

Defines what happens after the pore is activated and Cytochrome C and Smac are released.

Uses CytoC, Smac, Apaf, Apop, C3, C6, C8, C9, PARP, XIAP monomers and their associated parameters to generate the rules that describe apoptosome formation, XIAP inhibition, activation of caspases (including caspase-6-mediated feedback), and cleavage of effector caspase substrates as specified in EARM 1.0.

Declares initial conditions for CytoC, Smac, Apaf-1, Apoptosome, caspases 3, 6, and 9, XIAP, and PARP.

earm.albeck_modules.Bax_tetramerizes(bax_active_state='A', rate_scaling_factor=1)

Creates rules for the rxns Bax + Bax <> Bax2, and Bax2 + Bax2 <> Bax4.

Parameters:

bax_active_state : string: ‘A’ or ‘M’

The state value that should be assigned to the site “state” for dimerization and tetramerization to occur.

rate_scaling_factor : number

A scaling factor applied to the forward rate constants for dimerization and tetramerization.

earm.albeck_modules.Bcl2_binds_Bax1_Bax2_and_Bax4(bax_active_state='A', rate_scaling_factor=1)

Creates rules for binding of Bcl2 to Bax monomers and oligomers.

Parameters:

bax_active_state : string: ‘A’ or ‘M’

The state value that should be assigned to the site “state” for the Bax subunits in the pore.

rate_scaling_factor : number

A scaling factor applied to the forward rate constants for binding between Bax (monomers, oligomers) and Bcl2.

earm.albeck_modules.albeck_11b(do_pore_transport=True)

Minimal MOMP model shown in Figure 11b.

Features:

• Bid activates Bax
• Active Bax is inhibited by Bcl2
• Free active Bax binds to and transports Smac to the cytosol

earm.albeck_modules.albeck_11c(do_pore_transport=True)

Model incorporating Bax oligomerization.

Features:

• Bid activates Bax
• Active Bax dimerizes; Bax dimers dimerize to form tetramers
• Bcl2 binds/inhibits Bax monomers, dimers, and tetramers
• Bax tetramers bind to and transport Smac to the cytosol

earm.albeck_modules.albeck_11d(do_pore_transport=True)

Model incorporating mitochondrial transport.

Features:

• Bid activates Bax
• Active Bax translocates to the mitochondria
• All reactions on the mito membrane have increased association rates
• Mitochondrial Bax dimerizes; Bax dimers dimerize to form tetramers
• Bcl2 binds/inhibits Bax monomers, dimers, and tetramers
• Bax tetramers bind to and transport Smac to the cytosol

earm.albeck_modules.albeck_11e(do_pore_transport=True)

Model incorporating mitochondrial transport and pore “insertion.”

Features:

• Bid activates Bax
• Active Bax translocates to the mitochondria
• All reactions on the mitochondria have increased association rates
• Mitochondrial Bax dimerizes; Bax dimers dimerize to form tetramers
• Bcl2 binds/inhibits Bax monomers, dimers, and tetramers
• Bax tetramers bind to mitochondrial “sites” and become active pores
• Active pores bind to and transport Smac to the cytosol

earm.albeck_modules.albeck_11f(do_pore_transport=True)

Model as in 11e, but with cooperative assembly of Bax pores.

Association rate constants for Bax dimerization, tetramerization, and insertion are set so that they increase at each step (from 1e-8 to 1e-7 and then 1e-6), thereby creating cooperative assembly.

See also the documentation for albeck_11e().