COX16 (cytochrome c oxidase assembly protein COX16 homolog, mitochondrial) is a small (106 aa) single-pass mitochondrial inner-membrane protein that acts as a non-catalytic assembly factor for respiratory chain complex IV (cytochrome c oxidase, COX). It is anchored in the inner membrane with its N-terminus in the matrix and its C-terminus in the intermembrane space. COX16 is required for cytochrome c oxidase biogenesis and is implicated in maturation of the mitochondrially encoded core subunit MT-CO2 (COX2), specifically in formation of its CuA copper center, interacting with newly synthesized MT-CO2 and with the copper-delivery metallochaperones SCO1, SCO2 and COA6, and being required for recruitment of SCO1 (but not SCO2) to the COX2 module. COX16 also escorts the COX2 assembly module onto the COX1-containing MITRAC intermediate, thereby helping merge the COX1 and COX2 assembly lines, but does not act on assembled respiratory supercomplexes. It lacks a canonical copper-binding motif and has no known catalytic activity. Loss-of-function variants cause autosomal-recessive mitochondrial complex IV deficiency (nuclear type 22; MC4DN22), presenting with hypertrophic cardiomyopathy, encephalopathy, fatal lactic acidosis and liver dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing COX16 at the mitochondrial inner membrane, where it acts as a COX assembly factor. This is directly supported by experimental submitochondrial localization and matches the UniProt subcellular location. Reason: COX16 was shown experimentally to be an inner mitochondrial membrane protein (protease-protection, carbonate-resistant, single transmembrane span). The IBA is consistent with the two independent IDA primaries and the UniProt record, and represents the core cellular location where the gene product acts. Supporting Evidence: PMID:29381136 COX16 was resistant to carbonate extraction PMID:29381136 inner mitochondrial membrane protein with its C-terminus facing the intermembrane space |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to complex IV assembly, the conserved core biological process of the COX16 family from yeast to human and worm. This is strongly corroborated by experimental knockout/knockdown data. Reason: This is the core function of COX16. Loss of COX16 impairs cytochrome c oxidase assembly in human cells and produces COX deficiency in C. elegans, consistent with the phylogenetic inference across the COX16 family. Supporting Evidence: PMID:29381136 COX16 is required for cytochrome c oxidase biogenesis PMID:29355485 ablation in HEK293 cells impairs COX assembly |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to the mitochondrial inner membrane derived from the UniProt Subcellular Location vocabulary (SL-0168). Correct and specific. Reason: The UniProt-Subcell mapping matches the experimentally determined single-pass inner-membrane localization of COX16. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation (IPR020164, COX16 family) to the more general term mitochondrial membrane. Reason: Not wrong, but a parent of the more specific and experimentally supported GO:0005743 (mitochondrial inner membrane). Retained as a correct broader IEA; the inner-membrane term is the informative location. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a high-throughput binary interactome (yeast two-hybrid) map, recording a COX16 (Q9P0S2) interaction with FAM25A (B3EWG3). Reason: Bare 'protein binding' is uninformative and does not describe a molecular function. This particular interactor (FAM25A) has no established role in COX assembly and the interaction comes from a large-scale binary screen; per curation policy the annotation is not removed but is flagged as an over-annotation. The cached publication is a genome-scale dataset paper that does not name COX16 in its narrative text, so the specific interaction is not independently verifiable from the cache; supporting evidence is taken from the UniProt-recorded IntAct interaction. Supporting Evidence: file:human/COX16/COX16-uniprot.txt Q9P0S2; B3EWG3: FAM25A |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: IDA localization to mitochondrion from immunofluorescence curation (Human Protein Atlas). Reason: Correct but less specific than the experimentally supported inner-membrane localization. Retained as an accurate (if general) location annotation. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomic (HTP) localization of COX16 to the mitochondrion, from a quantitative high-confidence human mitochondrial proteome study. Reason: Consistent with the established mitochondrial (inner-membrane) localization. The cited paper is a proteome-scale dataset in which COX16 is one of thousands of proteins and is not named in the cached narrative text, but the mitochondrial assignment agrees with the specific IDA/IEA inner-membrane annotations; term is correct though less specific than GO:0005743. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:29355485 COX16 is required for assembly of cytochrome c oxidase in hu... | MARK AS OVER ANNOTATED | Summary: IPI annotation recording the experimentally demonstrated interaction of COX16 with MT-CO2/COX2 (P00403) by co-immunoprecipitation. Reason: The underlying experiment (co-IP of COX16 with COX2) is genuine and biologically important, but the generic 'protein binding' term is uninformative as a molecular function. Per policy the experimental annotation is not removed; the interaction instead supports the assembly-factor biological process (GO:0033617) and is captured there. Flagged as over-annotated at the MF level. Supporting Evidence: PMID:29355485 COX16 co-immunoprecipitates |
| GO:0005515 protein binding | IPI PMID:29381136 COX16 promotes COX2 metallation and assembly during respirat... | MARK AS OVER ANNOTATED | Summary: IPI annotation covering the experimentally demonstrated interactions of COX16 with the COX2 copper-delivery machinery, including SCO2 (O43819), SCO1 (O75880), MT-CO2/COX2 (P00403) and COA6 (Q5JTJ3). Reason: These are real, well-characterized experimental interactions central to COX16 function (SCO1/SCO2/COA6/MT-CO2), but 'protein binding' is a non-informative molecular-function term. The interactions are what implicate COX16 in CuA-site formation and are represented biologically by the complex IV assembly process annotation. Retained (not removed) but marked as over-annotated at the MF level. Supporting Evidence: PMID:29381136 COX16 coisolated with SCO1 and COA6 in immunoisolations from wild type cells, indicating that these proteins form a complex PMID:29381136 COX16 solely associated with the newly synthesized COX2 |
| GO:0005743 mitochondrial inner membrane | IDA PMID:29355485 COX16 is required for assembly of cytochrome c oxidase in hu... | ACCEPT | Summary: Direct experimental (IDA) localization of COX16 to the mitochondrial inner membrane, from the human COX16 characterization study. Reason: Core, experimentally established location. COX16 is a small transmembrane protein of the inner membrane facing the intermembrane space. Supporting Evidence: PMID:29355485 human COX16 encodes a small mitochondrial transmembrane protein |
| GO:0005743 mitochondrial inner membrane | IDA PMID:29381136 COX16 promotes COX2 metallation and assembly during respirat... | ACCEPT | Summary: Direct experimental (IDA) localization of COX16 to the mitochondrial inner membrane, established by protease-protection and carbonate-extraction assays. Reason: Core, experimentally established location, independently confirming the inner-membrane single-pass topology with the C-terminus in the intermembrane space. Supporting Evidence: PMID:29381136 COX16 was present in isolated mitochondria and only became accessible to protease treatment when the outer membrane was disrupted PMID:29381136 inner mitochondrial membrane protein with its C-terminus facing the intermembrane space |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:29355485 COX16 is required for assembly of cytochrome c oxidase in hu... | ACCEPT | Summary: IMP annotation to complex IV assembly based on loss-of-function phenotypes (COX16 knockout in HEK293 cells and knockdown in C. elegans impairing COX assembly/activity). Reason: Core biological process, directly supported by mutant/knockout phenotypes showing impaired COX assembly. Supporting Evidence: PMID:29355485 ablation in HEK293 cells impairs COX assembly |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IDA PMID:29381136 COX16 promotes COX2 metallation and assembly during respirat... | ACCEPT | Summary: IDA annotation to complex IV assembly, from direct demonstration that COX16 is required for COX2 maturation, SCO1 recruitment (CuA-site formation), and integration of COX2 into COX1-containing MITRAC intermediates. Reason: Core biological process. COX16 is required for cytochrome c oxidase biogenesis and specifically for COX2 assembly/metallation, implicating it in CuA-site formation and in merging the COX1 and COX2 assembly lines. Supporting Evidence: PMID:29381136 COX16 is required for cytochrome c oxidase biogenesis PMID:29381136 COX16 is required for SCO1 but not SCO2 association with COX2, implicating COX16 in CuA site formation |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865449 | ACCEPT | Summary: TAS (Reactome) location annotation placing COX16 at the mitochondrial inner membrane within the Complex IV assembly reaction "Metallochaperone inserts Cu2+ into MT-CO1". Reason: Consistent with the experimentally established inner-membrane localization of COX16 within the COX assembly pathway. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865579 | ACCEPT | Summary: TAS (Reactome) location annotation placing COX16 at the mitochondrial inner membrane within the reaction "MT-CO1 and MT-CO2 complexes associate, installing heme moieties". Reason: Consistent with the experimentally established inner-membrane localization of COX16 within the COX assembly pathway. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865630 | ACCEPT | Summary: TAS (Reactome) location annotation placing COX16 at the mitochondrial inner membrane within the reaction "Metallochaperone inserts 2Cu2+ into MT-CO2". Reason: Consistent with the experimentally established inner-membrane localization of COX16 and directly relevant to its role in MT-CO2 copper delivery/CuA-site formation. Supporting Evidence: file:human/COX16/COX16-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0003674 molecular_function | ND GO_REF:0000015 | MARK AS OVER ANNOTATED | Summary: Root-node ND placeholder recording that no molecular function had been determined at the time of annotation. Reason: This ND placeholder is now largely superseded by the established assembly-factor role. COX16 is a non-catalytic chaperone-like assembly factor with no canonical copper-binding motif and no known catalytic molecular function, so no informative MF term is asserted; the placeholder is flagged rather than removed. Supporting Evidence: file:human/COX16/COX16-uniprot.txt Belongs to the COX16 family |
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