COX20 (also known as FAM36A) is a small (118 aa) multi-pass protein of the mitochondrial inner membrane that acts as a non-catalytic assembly chaperone for cytochrome c oxidase (respiratory chain complex IV, CIV), specific to the core catalytic subunit MT-CO2 (COX2). Following its mitochondrial synthesis, MT-CO2 engages COX20, which binds and stabilises the newly synthesised protein during insertion of its N-proximal transmembrane domain and chaperones it through membrane insertion and maturation of its binuclear copper CuA centre by the metallochaperones SCO1 and SCO2 (together with COA6, COX18 and TMEM177), delivering mature MT-CO2 into the assembling CIV holoenzyme. COX20 has no known catalytic activity; its role is to hold and present MT-CO2 to the copper metallation machinery. Loss of COX20 causes a severe, isolated CIV deficiency in which cells accumulate CIV subassemblies containing COX1/COX4 but lacking COX2. Biallelic loss-of-function variants cause mitochondrial complex IV deficiency, nuclear type 11 (MC4DN11), an autosomal recessive disorder with childhood/adolescent onset presenting with cerebellar ataxia, dystonia, choreoathetotic movements, dysarthria and muscle hypotonia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing COX20 in the mitochondrion. This is correct but is the general organelle term; COX20 acts specifically at the mitochondrial inner membrane (GO:0005743), which is annotated experimentally. Reason: COX20 is a well-established mitochondrial protein; the IBA annotation is accurate at the organelle level, though non-core relative to the more precise inner-membrane localization. Supporting Evidence: PMID:29154948 Upon synthesis, COX2 engages with COX20 in the inner mitochondrial membrane, a scaffold protein that recruits metallochaperones for copper delivery to the CuA-Site of COX2. |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to mitochondrial respiratory chain complex IV assembly. This is the core biological process of COX20 and is strongly corroborated by human experimental data (IMP) and by conserved function across the COX20 family. Reason: Direct experimental evidence in human cells establishes COX20 as required for complex IV assembly; the IBA annotation is at the correct level of specificity and represents the gene's core function. Supporting Evidence: PMID:23125284 These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) annotation of inner-membrane localization based on InterPro/UniProt-SubCell mapping. This matches the experimentally determined subcellular location and the multi-pass topology of the protein. Reason: COX20 is an inner mitochondrial membrane multi-pass protein; the electronic inner-membrane assignment agrees with experimental (IDA/EXP) evidence and is the core location. Supporting Evidence: file:human/COX20/COX20-uniprot.txt Mitochondrion inner membrane |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (IEA) InterPro2GO annotation to complex IV assembly, derived from the Cox20 InterPro signature (IPR022533). This is consistent with the experimentally supported core function. Reason: The InterPro Cox20 family signature reliably predicts a role in cytochrome c oxidase assembly; this agrees with the experimental IMP annotations. Supporting Evidence: PMID:24403053 We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the HuRI large-scale binary (yeast two-hybrid) interactome map. The listed partners (AQP6, CHIA, CREB3L1, DYNC1H1, ERGIC3, FUNDC2, GET1, GJA8, GOLT1A, JAGN1, MAOB, MENT, NCBP2AS2, PGRMC2, SLC10A1, SLC10A6, TCEA2, TEX44, TMEM35A, TMX2) are overwhelmingly non-mitochondrial secretory/plasma-membrane proteins with no relationship to complex IV assembly; these are high-throughput screen hits, not functional partners. Reason: Uninformative "protein binding" from a proteome-wide Y2H screen; the interactors are biologically unrelated to COX20's function and the term adds no functional information. Retained as over-annotated rather than removed, as it derives from experimental IPI evidence. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) localization to mitochondrion. Correct but at the organelle level; the experimentally resolved location is the inner membrane. Reason: Accurate organelle-level localization consistent with all other evidence, though non-core relative to the more specific inner-membrane term. Supporting Evidence: PMID:29154948 Upon synthesis, COX2 engages with COX20 in the inner mitochondrial membrane, a scaffold protein that recruits metallochaperones for copper delivery to the CuA-Site of COX2. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput identification of COX20 in the high-confidence human mitochondrial proteome (MitoCoP). Confirms mitochondrial residence at the organelle level. Reason: COX20 is a bona fide mitochondrial protein captured in a rigorous quantitative mitochondrial proteome; consistent with all other evidence, non-core relative to the inner-membrane term. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005743 mitochondrial inner membrane | EXP PMID:29154948 The mitochondrial TMEM177 associates with COX20 during COX2 ... | ACCEPT | Summary: Experimental localization of COX20 to the mitochondrial inner membrane, where it acts as the MT-CO2 assembly scaffold. This is the core subcellular location. Reason: Directly demonstrated inner-membrane localization consistent with the protein's multi-pass topology and its role in MT-CO2 membrane insertion and copper metallation. Supporting Evidence: PMID:29154948 Upon synthesis, COX2 engages with COX20 in the inner mitochondrial membrane, a scaffold protein that recruits metallochaperones for copper delivery to the CuA-Site of COX2. PMID:29154948 residing in the inner membrane |
| GO:0005515 protein binding | IPI PMID:23125284 A mutation in the FAM36A gene, the human ortholog of COX20, ... | MARK AS OVER ANNOTATED | Summary: "Protein binding" (IPI) recording the physiologically important interaction of COX20 with newly synthesised MT-CO2/COX2, demonstrated by co-purification. The interaction is central to COX20's function, but the bare GO:0005515 term does not convey that; the biology is captured by the complex IV assembly BP. Reason: The MT-CO2 interaction is real and functionally central, but "protein binding" is uninformative as a molecular-function annotation. Marked as over-annotated (not removed) since it is supported by experimental IPI evidence; the functional content is represented by GO:0033617. Supporting Evidence: PMID:23125284 We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit. |
| GO:0005515 protein binding | IPI PMID:24403053 Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and... | MARK AS OVER ANNOTATED | Summary: "Protein binding" (IPI) capturing the interactions of COX20 with newly synthesised COX2 and with the SCO1/SCO2 metallochaperone module during CIV assembly. Functionally important interactions, but the bare term is uninformative. Reason: Genuine, functionally central interactions (COX2, SCO1/SCO2) supported by experimental IPI, but "protein binding" adds no molecular-function information; the biology is represented by the complex IV assembly BP. Supporting Evidence: PMID:24403053 Additionally, we show that SCO1 and SCO2 act on COX20-bound COX2. |
| GO:0005515 protein binding | IPI PMID:28330871 Human mitochondrial cytochrome c oxidase assembly factor COX... | MARK AS OVER ANNOTATED | Summary: "Protein binding" (IPI) for the interactions of COX20 within the MT-CO2 maturation module (COX2, COX18, SCO1/SCO2/COA6). Functionally central but uninformative as a molecular-function term. Reason: Real, mechanistically important interactions supported by experimental IPI, but the bare "protein binding" term conveys no molecular function; captured instead by the complex IV assembly BP. Supporting Evidence: PMID:28330871 The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis. |
| GO:0005515 protein binding | IPI PMID:29154948 The mitochondrial TMEM177 associates with COX20 during COX2 ... | MARK AS OVER ANNOTATED | Summary: "Protein binding" (IPI) for the COX20 interaction network including TMEM177, COA6, MT-CO2, SCO1 and SCO2 during COX2 biogenesis. Functionally relevant but uninformative as a molecular-function annotation. Reason: Physiologically meaningful interactions supported by experimental IPI, but "protein binding" provides no molecular-function content; the biology is represented by the complex IV assembly BP. Supporting Evidence: PMID:29154948 TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:23125284 A mutation in the FAM36A gene, the human ortholog of COX20, ... | ACCEPT | Summary: Direct experimental (IDA) localization of COX20 to the mitochondrial inner membrane, consistent with its topology and MT-CO2 chaperone role. Core location. Reason: Directly demonstrated inner-membrane localization; agrees with the multi-pass membrane topology and independent experimental data. Supporting Evidence: PMID:29154948 residing in the inner membrane |
| GO:0005743 mitochondrial inner membrane | IDA PMID:24403053 Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and... | ACCEPT | Summary: Direct experimental (IDA) localization of COX20 to the mitochondrial inner membrane, where it stabilises MT-CO2 and presents it to the copper metallochaperones. Core location. Reason: Independent experimental confirmation of inner-membrane localization, consistent with all other evidence and the protein's function. Supporting Evidence: PMID:24403053 These cell lines exhibit a severe, isolated CIV deficiency due to instability of COX2, a mitochondrion-encoded CIV subunit. PMID:29154948 residing in the inner membrane |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:23125284 A mutation in the FAM36A gene, the human ortholog of COX20, ... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence: a homozygous FAM36A/COX20 mutation causes complex IV deficiency, with cells accumulating COX1-containing CIV subassemblies devoid of COX2. Establishes COX20's core role in CIV assembly. Reason: Loss-of-function in patient cells directly demonstrates that COX20 is required for cytochrome c oxidase (complex IV) assembly; this is the core biological process. Supporting Evidence: PMID:23125284 Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein. PMID:23125284 These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency. |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:24403053 Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence from COX20 knockdown/knockout human cell lines showing severe isolated CIV deficiency due to COX2 instability, with accumulation of COX1/COX4 subassemblies. Confirms the core assembly role. Reason: Independent loss-of-function evidence establishes COX20 as required for complex IV assembly, acting as a chaperone that stabilises MT-CO2 and presents it to the copper metallation module. Supporting Evidence: PMID:24403053 These cell lines exhibit a severe, isolated CIV deficiency due to instability of COX2, a mitochondrion-encoded CIV subunit. PMID:24403053 We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865630 | ACCEPT | Summary: Reactome traceable-author (TAS) inner-membrane localization associated with the reaction in which the metallochaperone inserts copper into MT-CO2. COX20 operates at the inner membrane in this step. Consistent with experimental data. Reason: Curated pathway evidence agreeing with the experimentally determined inner-membrane location. Supporting Evidence: PMID:29154948 Upon synthesis, COX2 engages with COX20 in the inner mitochondrial membrane, a scaffold protein that recruits metallochaperones for copper delivery to the CuA-Site of COX2. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9902096 | ACCEPT | Summary: Reactome traceable-author (TAS) inner-membrane localization for the reaction in which COX18 inserts nascent MT-CO2 into the COX20:TMEM177 chaperone complex. COX20 acts at the inner membrane. Consistent with experimental data. Reason: Curated pathway evidence agreeing with the experimentally determined inner-membrane location and COX20's chaperone role in MT-CO2 biogenesis. Supporting Evidence: PMID:28330871 We demonstrate that COX20 stabilizes COX2 during insertion of its N-proximal transmembrane domain |
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