ccmC

Summary: The CcmC-associated catalase phenotype does not resolve intrinsic catalase or direct oxidant-detoxification activity.

Reason: The PAINT assertion at PTN001247822 is a phylogenetic claim, not weakened by donor count. The traceable P. aeruginosa source PMID:18174132 reports undetectable catalase production in a ccmC mutant alongside broad heme-related phenotypes. This is compatible with indirect impairment of catalases and does not establish CcmC catalysis. Full text could not be accessed, so the previous confident source-defect/removal is replaced by uncertainty. The dependent oxidant-detoxification inference is likewise unresolved.

Summary: Co-immunoprecipitation of CcmC with the heme chaperone CcmE (P69490), reported in a study focused on the CcmF/CcmH heme lyase complex.

Reason: The CcmC-CcmE interaction is real and well established, but bare protein binding conveys no functional information. The informative content of this interaction (heme transfer from CcmC to CcmE) is captured by heme binding, protein-heme linkage and cytochrome c biosynthetic process annotations. Removal follows the generic protein-binding policy and does not dispute the interaction.

Summary: CcmC co-immunoprecipitates with CcmD (P0ABM5) in a ternary CcmCDE complex.

Reason: The CcmCD interaction is supported, but the bare protein-binding term is uninformative. The functional context (CcmCDE heme-loading complex) is captured by the process annotations and core function. Removal follows the protein-binding policy and does not dispute the interaction.

Summary: CcmC interacts with CcmE (P69490) within the ternary CcmCDE complex.

Reason: Bare protein binding is uninformative; the CcmC-CcmE interaction is functionally the heme-loading step, captured by heme binding and protein-heme linkage. Removal follows the protein-binding policy and does not dispute the interaction.

Summary: CcmC co-precipitates with membrane-anchor-swapped and soluble forms of CcmE (P69490), mapping the interaction to the CcmE periplasmic domain.

Reason: Real interaction, uninformative term. Removal follows the protein-binding policy; the functional content is the heme-loading role of CcmC.

Summary: CcmC associates with the ATPase subunit CcmA (P33931) in a CcmA2B1C1 complex.

Reason: The CcmA-CcmC association is real (CcmA2B1C1 complex), but bare protein binding is uninformative. Complex membership is captured by the ABC transporter complex annotation. Removal follows the protein-binding policy.

Summary: Holo-CcmE (P69490) is trapped bound to CcmC in a stable dead-end complex when CcmA or CcmB is absent.

Reason: Real interaction, uninformative term. The paper's informative finding is high-affinity heme binding by CcmC, which is captured by GO:0020037. Removal follows the protein-binding policy.

Summary: CcmD (P0ABM5) copurifies with CcmC as part of the CcmABCD release complex.

Reason: Real interaction, uninformative term; complex membership is represented by the complex annotation. Removal follows the protein-binding policy.

Summary: GST-CcmA (P33931) copurifies with His-tagged CcmC.

Reason: Real interaction, uninformative term; complex membership is represented by the complex annotation. Removal follows the protein-binding policy.

Summary: CcmC and CcmE (P69490) were purified together as a heme-containing CcmCDE complex in which CcmC provides the heme axial ligands.

Reason: Real interaction, uninformative term. The functional content (CcmC binds heme and is the active site for holo-CcmE adduct formation) is captured by heme binding and protein-heme linkage. Removal follows the protein-binding policy.

Summary: CcmC is an integral protein of the bacterial inner (plasma) membrane.

Reason: Correct and appropriately specific; CcmC acts in the cytoplasmic membrane with its heme-binding WWD domain facing the periplasm. The target's own experimental localization is among the descendant evidence for this node.

Summary: Global E. coli inner membrane topology study including CcmC.

Reason: The study experimentally assigned C-terminal locations for E. coli inner membrane proteins; CcmC is a well-established inner membrane protein (UniProt cites this study for its topology). Abstract-only cache, but the localization is fully consistent with all other evidence.

Summary: UniProt subcellular location mapping to plasma membrane.

Reason: Consistent with experimental and topology evidence for an inner-membrane location.

Summary: Sequence-model (six transmembrane helices) support for inner-membrane location.

Reason: Correct and consistent with the other plasma membrane rows.

Summary: ccmC heme transmembrane transporter activity remains unresolved in competing system I models.

Reason: Engineered E. coli CcmCD cysteine/heme crosslinks support a cytoplasmic acceptance site and membrane-spanning channel, materially strengthening a CcmC transport model. They map heme proximity in an occupancy-biased construct rather than directly measuring directional flux; competing CcmB/CcmBC models remain unresolved. CcmC heme binding and CcmE loading are accepted independently. The E. coli evidence is distinguished from heterologous ortholog assays and engineered expression constructs.

Summary: ccmC contributes to directed heme handoff within the maturation machinery.

Reason: CcmC binds and positions heme for transfer to the CcmE chaperone. GO:0015886 includes directed movement of heme within a cell; it does not require transmembrane transport. These active handoff/release roles support the process without deciding which subunit conducts heme across the membrane. The E. coli evidence is distinguished from heterologous ortholog assays and engineered expression constructs.

Summary: ccmC acts at the bacterial plasma membrane.

Reason: CcmC has experimentally supported integral membrane topology with six helices. This supports the inner-membrane location independently of heme-ligand chemistry. The supported inner membrane is the more specific replacement for generic membrane.

Proposed replacements: plasma membrane

Summary: CcmC positions heme in its WWD domain so that the heme 2-vinyl group is covalently attached to His130 of CcmE.

Reason: Direct crosslinking and structural mapping show heme bound in the CcmC WWD domain in a specific orientation for covalent attachment to CcmE; CcmC is necessary and sufficient for covalent heme incorporation into CcmE. CcmC therefore does part of the work of forming the heme-protein covalent bond (positioning the heme as an active site), not merely being required for it. CcmE is not a cytochrome, so the general protein-heme linkage term is the right level rather than cytochrome c-heme linkage.

Summary: CcmC participates in c-type cytochrome biogenesis.

Reason: The InterPro mapping captures the right pathway at the wrong term. Cytochrome complex assembly describes assembling a complex that contains a cytochrome; CcmC acts upstream, loading heme onto CcmE for the synthesis of holocytochrome c. GO:1903607 cytochrome c biosynthetic process, already carried with IMP and IBA support, is the appropriate process. The descendant GO:0018063 cytochrome c-heme linkage is not chosen because CcmC does not attach heme to apocytochrome c itself (that is done by CcmF/CcmH).

Proposed replacements: cytochrome c biosynthetic process

Summary: Author statement placing CcmC in heme delivery for cytochrome c assembly.

Reason: Same claim as the IEA row; the better term for CcmC's role is cytochrome c biosynthetic process (GO:1903607).

Proposed replacements: cytochrome c biosynthetic process

Summary: CcmC binds heme directly.

Reason: Direct heme binding by CcmC was shown biochemically and later confirmed by purification of heme-containing CcmCDE complexes with CcmC His60/His184 as axial ligands and by in vivo heme crosslinking to the WWD domain. This is the core molecular function of CcmC.

Summary: InterPro CcsA/CcmC family mapping to heme binding.

Reason: Consistent with direct experimental evidence for heme binding by E. coli CcmC.

Summary: CcmABCD/E assembly is demonstrated, but its fit to an ATP-binding cassette transporter complex remains mechanistically contested.

Reason: Structures establish association with the ABC-family machinery, including bound CcmE. GO:0043190 describes a metabolite-transport complex, not just ABC architecture. The 2023 floppase interpretation and 2025 ATP-independent CcmCD/ATP-dependent release interpretation disagree about coupling and conduit. Retain uncertainty about this functional complex class rather than treating the older rejection or the newer architecture as decisive.

Summary: The CcmC-associated catalase phenotype does not resolve intrinsic catalase or direct oxidant-detoxification activity.

Reason: The PAINT assertion at PTN001247822 is a phylogenetic claim, not weakened by donor count. The traceable P. aeruginosa source PMID:18174132 reports undetectable catalase production in a ccmC mutant alongside broad heme-related phenotypes. This is compatible with indirect impairment of catalases and does not establish CcmC catalysis. Full text could not be accessed, so the previous confident source-defect/removal is replaced by uncertainty. The dependent oxidant-detoxification inference is likewise unresolved.

Summary: CcmC-family proteins act in system I cytochrome c maturation.

Reason: Correct core process. E. coli CcmC's own experimental annotation is the descendant evidence for this node, as expected for a well-studied family member.

Summary: Chromosomal ccmC deletion abolishes holo-CcmE and holocytochrome c formation, restored by plasmid ccmC.

Reason: Core process. CcmC performs the heme-loading step of the pathway (heme binding and covalent transfer to CcmE), so it participates in, rather than being merely required for, cytochrome c biosynthesis.

Summary: The asserted heme import direction is opposite to the system I maturation route.

Reason: The checked GO definition requires movement from outside the cell across the plasma membrane into the cytosol. System I handles cytoplasmically synthesized heme for periplasmic maturation. Neither competing export model supports cytosolic import. This direction mismatch, rather than a blanket rejection of heme transport, is the reason for removal.