BCL2-family mitochondrial outer membrane permeabilization control module

Mammalian BCL2-family proteins control mitochondrial outer membrane permeabilization during intrinsic apoptosis. BH3-only proteins activate or derepress the pore-forming effectors BAX and BAK, while pro-survival BCL2-like proteins bind BH3 helices to sequester activators and effectors. When BH3-only activity overwhelms the pro-survival buffer, BAX and BAK oligomerize at the mitochondrial outer membrane to release cytochrome c and other intermembrane-space proteins into the apoptotic execution pathway.

MODULE:bcl2_family_momp_controlDRAFTRegulatory Stepmodules/bcl2_family_momp_control.yaml

mitochondrial outer membrane permeabilizationGO:0097345

file:projects/APOPTOSIS.md

Apoptosis project page

The APOPTOSIS project identified BAX, BAK1, BCL2, BCL2L1, MCL1, BID, BCL2L11, BBC3, and PMAIP1 as the reviewed mammalian BCL2-family set for explicit MOMP modeling.

GO:0097345

mitochondrial outer membrane permeabilization

The module is grounded in the GO biological-process term for permeabilization of the mitochondrial outer membrane.

GO:1901029

negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway

Pro-survival BCL2-family proteins act directly on the mitochondrial MOMP switch by inhibiting BAX/BAK activation and pore formation.

GO:1901030

positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway

BH3-only proteins promote the BAX/BAK MOMP switch by either directly activating pore-forming effectors or neutralizing pro-survival BCL2 proteins.

file:genes/human/BAX/BAX-ai-review.yaml

Human BAX AI gene review

Reviewed BAX core functions establish channel activity, BAX homodimerization, BH3-domain engagement, and heteromeric BCL2-family assemblies in mitochondrial outer membrane permeabilization.

file:genes/human/BAK1/BAK1-ai-review.yaml

Human BAK1 AI gene review

Reviewed BAK1 core functions establish apoptotic porin activity, homodimerization, BH3-domain engagement, and BCL2-family heteromeric assemblies in mitochondrial outer membrane permeabilization.

file:genes/human/BID/BID-ai-review.yaml

Human BID AI gene review

Reviewed BID core functions distinguish tBID as a cleaved BH3-only activator that links death-receptor and intrinsic signaling to BAX/BAK mitochondrial outer membrane permeabilization.

Created during the APOPTOSIS module pass after the individual human BCL2-family gene reviews were completed. The module is mammal-first and uses concrete human proteins as representatives; worm CED-9/EGL-1/CED-3/CED-4, Drosophila IAP/RHG/Dark/caspase wiring, and fungal metacaspase death are comparators rather than implied variants of this exact BAX/BAK/CYCS pathway.

4Nodes

3Parts

0Variant Sets

0Variants

11Annotons

3Connections

Derived QC

Recommended-field compliance

76.9% recommended fields populated

knowledge_gaps[0] · provenance (0/1)
knowledge_gaps[1] · provenance (0/1)
knowledge_gaps[2] · provenance (0/1)

Module deep research

✗ none found

No MODULE:bcl2_family_momp_control deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 7 evidence or coverage gap(s) (11 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
bax_pore_effector	BAX UniProtKB:Q07812 Gene	channel activity GO:0015267	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bak_pore_effector	BAK1 UniProtKB:Q16611 Gene	porin activity GO:0015288	Review Disagreement The review removes, modifies, or marks this term over-annotated and provides no retained/core support. Review the rationale; rejection of an evidence row alone is not a biological NOT.
bcl2_bh3_guardian	BCL2 UniProtKB:P10415 Gene	BH3 domain binding GO:0051434	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bcl2l1_bclxl_bh3_guardian	BCL2L1 UniProtKB:Q07817 Gene	BH3 domain binding GO:0051434	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcl1_bh3_guardian	MCL1 UniProtKB:Q07820 Gene	BH3 domain binding GO:0051434	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bid_tbid_direct_activator	BID UniProtKB:P55957 Gene	pro-apoptotic BCL2 family effector activator activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
bcl2l11_bim_dual_bh3	BCL2L11 UniProtKB:O43521 Gene	pro-survival BCL2 family protein inhibitor activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
bcl2l11_bim_direct_activator	BCL2L11 UniProtKB:O43521 Gene	pro-apoptotic BCL2 family effector activator activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
bbc3_puma_dual_bh3	BBC3 UniProtKB:Q9BXH1 Gene	pro-survival BCL2 family protein inhibitor activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
bbc3_puma_direct_activator	BBC3 UniProtKB:Q9BXH1 Gene	pro-apoptotic BCL2 family effector activator activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
pmaip1_noxa_mcl1_sensitizer	PMAIP1 UniProtKB:Q13794 Gene	pro-survival BCL2 family protein inhibitor activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

bh3_only_activation ⊣ pro_survival_bh3_sequestration [input]
bh3_only_activation is a negative regulator with no upstream edge (not described as feedback)
pro_survival_bh3_sequestration ⊣ bax_bak_pore_formation [input]
pro_survival_bh3_sequestration is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (9/9 grounded genes reviewed)

0 complete review(s) · 2 with deep research · 0 missing review · 7 reviewed but lacking deep research

Gene	Review	Complete	Deep research
BAK1 Q16611	✓	154/155	✗
BAX Q07812	✓	235/239	✗
BBC3 Q9BXH1	✓	58/65	✗
BCL2 P10415	✓	177/199	✓
BCL2L1 Q07817	✓	110/111	✓
BCL2L11 O43521	✓	82/110	✗
BID P55957	✓	82/104	✗
MCL1 Q07820	✓	100/117	✗
PMAIP1 Q13794	✓	50/58	✗

Tree

BCL2-family MOMP controlRegulatory Stepbcl2_family_momp_control

Parts
1. 1. BAX/BAK pore-forming effectors
2. BAX/BAK pore formationRegulatory Stepbax_bak_pore_formation
  
  Annotons
  - BAX pore-forming effector Gene Product: BAX
  - BAK pore-forming effector Gene Product: BAK1
3. 2. pro-survival BH3 sequestration
4. Pro-survival BH3 sequestrationRegulatory Steppro_survival_bh3_sequestration
  
  Annotons
  - BCL2 BH3-binding guardian Gene Product: BCL2
  - BCL2L1/Bcl-xL BH3-binding guardian Gene Product: BCL2L1
  - MCL1 BH3-binding guardian Gene Product: MCL1
5. 3. BH3-only activation and derepression
6. BH3-only activation and derepressionRegulatory Stepbh3_only_activation
  
  Annotons
  - BID/tBID direct activator Gene Product: BID
  - BIM direct activator and derepressor Gene Product: BCL2L11
  - BIM direct activator Gene Product: BCL2L11
  - PUMA direct activator and derepressor Gene Product: BBC3
  - PUMA direct activator Gene Product: BBC3
  - NOXA MCL1-selective derepressor Gene Product: PMAIP1

Details

Context

MammaliaNCBITaxon:40674

mitochondrial outer membraneGO:0005741 cytosolGO:0005829

BCL2-family MOMP controlRegulatory Stepbcl2_family_momp_control

mitochondrial outer membrane permeabilizationGO:0097345

Context

MammaliaNCBITaxon:40674

mitochondrial outer membraneGO:0005741 cytosolGO:0005829

Connections

bh3_only_activation -> pro_survival_bh3_sequestration Negatively Regulates

BH3-only sensitizers occupy pro-survival BCL2-family grooves and release BAX, BAK, or BH3-only activators from sequestration.

pro_survival_bh3_sequestration -> bax_bak_pore_formation Negatively Regulates

Pro-survival BCL2-like proteins restrain the pore-forming BAX/BAK effectors until the BH3-only signal exceeds the survival buffer.

bh3_only_activation -> bax_bak_pore_formation Positively Regulates

Direct-activator BH3 helices promote BAX/BAK conformational activation, homodimerization, and higher-order pore assembly.

Part 1: BAX/BAK pore-forming effectors

BAX/BAK pore formationRegulatory Stepbax_bak_pore_formation

Activated BAX and BAK insert into or rearrange within the mitochondrial outer membrane, homo-oligomerize, and form the membrane-permeabilizing pore.

Annotons

BAX pore-forming effector

bax_pore_effector

Participant: Gene Product: BAX

Gene Product:

BAXUniProtKB:Q07812

Function

channel activityGO:0015267

Targets: mitochondrial outer membrane

Processes

mitochondrial outer membrane permeabilizationGO:0097345 release of cytochrome c from mitochondriaGO:0001836

Locations

mitochondrial outer membraneGO:0005741

BH3-activated BAX homo-oligomerizes into a pore that releases cytochrome c during intrinsic apoptotic signaling.

BAK pore-forming effector

bak_pore_effector

Participant: Gene Product: BAK1

Gene Product:

BAK1UniProtKB:Q16611

Function

porin activityGO:0015288

Targets: mitochondrial outer membrane

Processes

mitochondrial outer membrane permeabilizationGO:0097345 release of cytochrome c from mitochondriaGO:0001836

Locations

mitochondrial outer membraneGO:0005741

Membrane-anchored BAK homo-oligomerizes into an apoptotic MOMP pore after BH3-only activation or release from pro-survival BCL2 relatives.

Part 2: pro-survival BH3 sequestration

Pro-survival BH3 sequestrationRegulatory Steppro_survival_bh3_sequestration

mitochondrial outer membraneGO:0005741

MCL-1L sequesters BAK, BAX, and BH3-only ligands at the mitochondrial outer membrane to prevent MOMP.

Part 3: BH3-only activation and derepression

BH3-only activation and derepressionRegulatory Stepbh3_only_activation

mitochondrial outer membraneGO:0005741

NOXA/PMAIP1 selectively binds pro-survival MCL1 and BCL2A1, derepressing BAX/BAK-dependent MOMP.