family_id: PANTHER:PTHR30071 family_name: HEME EXPORTER PROTEIN C preferred_name: CcmC/CcsA heme-handling membrane protein family summary: >- PTHR30071 groups polytopic membrane proteins that carry the periplasmic, tryptophan-rich "WWD" heme-handling domain. Its large subfamily SF1 contains both system I CcmC (E. coli, Pseudomonas, Haemophilus, Rhodobacter HelC, Bradyrhizobium CycZ, Arabidopsis mitochondrial CCMC) and system II ResC/CcsA (Bacillus subtilis ResC and chloroplast CcsA), while SF15 holds the B. subtilis HemX protein. In system I, CcmC binds heme with high affinity in its WWD domain and loads it covalently onto the heme chaperone CcmE in a CcmCDE complex; CcmAB ATP hydrolysis then releases holo-CcmE. In system II, the CcsA/ResC member of the subfamily forms part of the CcsBA heme-handling and ligation machinery. Heme binding through the WWD domain is therefore the conserved molecular feature of SF1, whereas the downstream role (holo-CcmE formation versus system II synthase) differs between the two systems. functional_coherence: MOSTLY_COHERENT coherence_reason: >- The WWD heme-binding feature and the cytochrome c biogenesis process are shared across SF1, but SF1 lumps system I CcmC with system II CcsA/ResC, whose mechanistic roles differ, and SF15 (HemX) is not established to work in cytochrome c biogenesis. A PAINT catalase-activity assertion at the family root is not consistent with the known biochemistry and is left unresolved. reference_protein: id: UniProtKB:P0ABM1 label: Heme exporter protein C gene_symbol: ccmC organism: Escherichia coli (strain K12) gene_review: genes/ECOLI/ccmC/ccmC-ai-review.yaml subfamilies: - subfamily_id: PANTHER:PTHR30071:SF1 label: CYTOCHROME B_B6 PROTEIN-RELATED diverged_from_family: false representative_members: - id: UniProtKB:P0ABM1 label: Heme exporter protein C gene_symbol: ccmC organism: Escherichia coli (strain K12) gene_review: genes/ECOLI/ccmC/ccmC-ai-review.yaml - id: UniProtKB:Q88EX7 label: Heme exporter protein C gene_symbol: ccmC organism: Pseudomonas putida KT2440 gene_review: genes/PSEPK/ccmC/ccmC-ai-review.yaml - id: UniProtKB:P35162 label: Cytochrome c biogenesis protein ResC gene_symbol: resC organism: Bacillus subtilis (strain 168) - id: UniProtKB:P56770 label: Cytochrome c biogenesis protein CcsA gene_symbol: ccsA organism: Arabidopsis thaliana - subfamily_id: PANTHER:PTHR30071:SF15 label: PROTEIN HEMX diverged_from_family: true divergence_description: >- B. subtilis HemX is the only Swiss-Prot member; it is encoded in the hemAXCDBL heme biosynthesis operon rather than with cytochrome c maturation genes, and no role in cytochrome c biogenesis or WWD heme handling is established for it. representative_members: - id: UniProtKB:P16645 label: Protein HemX gene_symbol: hemX organism: Bacillus subtilis (strain 168) node_assessments: - node_id: PANTHER:PTN001247822 asserted_term: id: GO:1903607 label: cytochrome c biosynthetic process evidence: IBD paint_snapshot: '20260424' seeds: - id: UniProtKB:P0ABM1 assessment: SOUND assessment_reason: >- Both system I CcmC and system II CcsA/ResC members of SF1 act in cytochrome c biogenesis; HemX (SF15) is the only member without established involvement, and PAINT may not place that branch below this node. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN001247822\tGO:1903607\tP\tIBD\tfalse\tUniProtKB:P0ABM1" - reference_id: PMID:29518410 supporting_text: >- System I is composed of eight integral membrane proteins (CcmA-H) and is proposed to transport heme via CcmC to an external "WWD" domain for presentation to the membrane-tethered heme chaperone, CcmE. - node_id: PANTHER:PTN001247822 asserted_term: id: GO:0005886 label: plasma membrane evidence: IBD paint_snapshot: '20260529' seeds: - id: UniProtKB:P0ABM1 - id: UniProtKB:P35162 assessment: SOUND assessment_reason: >- Bacterial members are polytopic inner-membrane proteins; the eukaryotic organellar members are excluded by the IRD rows at PTN008624019 and PTN008624028. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN001247822\tGO:0005886\tC\tIBD\tfalse\tUniProtKB:P0ABM1|UniProtKB:P35162" - node_id: PANTHER:PTN008624019 asserted_term: id: GO:0005886 label: plasma membrane evidence: IRD negated: true node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260529' seeds: - id: PANTHER:PTN001247822 assessment: LOSS_SUPPORTED assessment_reason: >- Eukaryotic members (mitochondrial CCMC, chloroplast CcsA) reside in organellar membranes, not the plasma membrane, so the location block is appropriate. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN008624019\tGO:0005886\tC\tIRD\ttrue\tPANTHER:PTN001247822\ttaxon:2759" - node_id: PANTHER:PTN008624028 asserted_term: id: GO:0005886 label: plasma membrane evidence: IRD negated: true paint_snapshot: '20260529' seeds: - id: PANTHER:PTN001247822 assessment: LOSS_SUPPORTED assessment_reason: >- A second organellar (non-plasma-membrane) clade blocked from the bacterial location assertion, consistent with the organellar localisation of plastid/mitochondrial members. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN008624028\tGO:0005886\tC\tIRD\ttrue\tPANTHER:PTN001247822" - node_id: PANTHER:PTN001247822 asserted_term: id: GO:0004096 label: catalase activity evidence: IBD paint_snapshot: '20260424' seeds: - id: UniProtKB:Q9I3N5 assessment: UNRESOLVED assessment_reason: >- The seed is a Pseudomonas aeruginosa CcmC IMP annotation citing PMID:16824107, whose cached abstract describes E. coli CcmABC-dependent release of holo-CcmE and does not mention catalase; the full text was not available here. CcmC has no catalase fold and its established activity is WWD-domain heme binding and transfer to CcmE, so a catalase phenotype would most plausibly be an indirect consequence of a cytochrome c defect. Propagation of catalase activity to the whole family is not supported by the family biochemistry, but the seed evidence could not be inspected. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN001247822\tGO:0004096\tF\tIBD\tfalse\tUniProtKB:Q9I3N5" term_assessments: - assessed_term: id: GO:0020037 label: heme binding scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR30071:SF1 label: CYTOCHROME B_B6 PROTEIN-RELATED scope_reason: >- Heme binding in the periplasmic WWD domain is demonstrated for E. coli CcmC and is the shared feature of the CcmC/CcsA members of SF1; it is not established for HemX (SF15). supported_by: - reference_id: PMID:16824107 supporting_text: >- In the absence of CcmA or CcmB, holo(haem)CcmE binds to CcmC in a stable dead-end complex, indicating high affinity binding of haem to CcmC. - reference_id: PMID:29518410 supporting_text: >- we develop a new cysteine/heme crosslinking approach to trap and map endogenous heme in CcmC (WWD domain) - assessed_term: id: GO:1903607 label: cytochrome c biosynthetic process scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR30071:SF1 label: CYTOCHROME B_B6 PROTEIN-RELATED scope_reason: >- Established for system I CcmC and system II CcsA/ResC (SF1), not for HemX (SF15). supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN001247822\tGO:1903607\tP\tIBD\tfalse\tUniProtKB:P0ABM1" - assessed_term: id: GO:0004096 label: catalase activity scope: UNRESOLVED scope_reason: >- Rests on a single IMP seed whose cited publication could not be checked; catalase activity is not part of the known CcmC/CcsA biochemistry. supported_by: - reference_id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv supporting_text: "PTHR30071\tPTN001247822\tGO:0004096\tF\tIBD\tfalse\tUniProtKB:Q9I3N5" references: - id: file:interpro/panther/PTHR30071/PTHR30071-paint.tsv title: PANTHER PAINT annotations for PTHR30071 (HEME EXPORTER PROTEIN C) - id: file:interpro/panther/PTHR30071/PTHR30071-entries.csv title: UniProtKB Swiss-Prot members of PTHR30071 - id: PMID:16824107 title: ABC transporter-mediated release of a haem chaperone allows cytochrome c biogenesis. - id: PMID:29518410 title: Structurally Mapping Endogenous Heme in the CcmCDE Membrane Complex for Cytochrome c Biogenesis. review_status: COMPLETE reviewed_by: claude-code review_date: '2026-10-23' notes: >- Reviewed as part of the bacterial cytochrome c maturation system I module, which grounds the CcmC role at PTHR30071:SF1 for heme binding only; the system I-specific role (holo-CcmE formation) is carried by the module, not asserted for the whole subfamily. The catalase IBD should be raised with PAINT curators.