GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

InterPro2GO mapping (COX6B family domains) propagates mitochondrial and Complex IV-related annotations to COX6B1.

GO_REF:0000033

Annotation inferences using phylogenetic trees

PAINT/IBA phylogenetic propagation supports Complex IV membership, mitochondrial inner-membrane localization, and cytochrome-c-to-O2 electron transport for COX6B1 across COX6B orthologs.

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

UniPathway UPA00705 (oxidative phosphorylation) propagates participation in the OXPHOS pathway to COX6B1.

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

Curated immunofluorescence data (Human Protein Atlas) place COX6B1 in mitochondria.

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

Logical inference from cytochrome-c oxidase activity (GO:0004129) propagates proton transmembrane transport (GO:1902600) to Complex IV subunits including COX6B1.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Combined automated IEA methods propagate inner mitochondrial membrane localization and Complex IV membership to COX6B1.

PMID:2172092

Isolation of cDNAs encoding subunit VIb of cytochrome c oxidase and steady-state levels of coxVIb mRNA in different tissues.

Cloned cDNAs encoding human cytochrome c oxidase subunit VIb (COX6B1) and characterized tissue-specific steady-state mRNA levels, identifying COX6B1 as a subunit of cytochrome c oxidase.

"Isolation of cDNAs encoding subunit VIb of cytochrome c oxidase and steady-state levels of coxVIb mRNA in different tissues."

PMID:22926577

Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis.

Quantitative proteomics of human substantia nigra in neurodegenerative disease detected COX6B1, used to underpin a substantia-nigra-development phenotype association (HEP evidence).

"Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's disease and Multiple sclerosis."

PMID:30030519

Structure of the intact 14-subunit human cytochrome c oxidase.

Cryo-EM structure (3.3 Å, PDB 5Z62) of human Complex IV confirms COX6B1 as a subunit of the intact 14-subunit holoenzyme on the intermembrane-space side and resolves its position at the dimer interface.

"we obtained the entire CIV structure containing 14 subunits, which includes the extra subunit NDUFA4"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

High-confidence mitochondrial proteome identifies COX6B1 as a mitochondrial protein.

"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context."

Reactome:R-HSA-163214

Electron transfer from reduced cytochrome c to molecular oxygen

Reactome pathway describing Complex IV electron transfer from reduced cytochrome c to O2 places COX6B1 in the inner mitochondrial membrane as a CIV subunit.

"Electron transfer from reduced cytochrome c to molecular oxygen"

Reactome:R-HSA-9709406

CO binds to Cytochrome c oxidase

Reactome pathway describing carbon monoxide binding to CIV places COX6B1 in the inner mitochondrial membrane as part of the target enzyme.

"CO binds to Cytochrome c oxidase"

Reactome:R-HSA-9865663

MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex

Reactome CIV assembly step in which COX6A, COX6B (including COX6B1), COX7A and NDUFA4 join the holo-MT-CO1,2 complex; places COX6B1 in the inner mitochondrial membrane during late CIV assembly.

"MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex"

file:human/COX6B1/COX6B1-deep-research-falcon.md

Falcon deep research for human COX6B1

COX6B1 is a small, nuclear-encoded accessory subunit of mitochondrial Complex IV and is not a catalytic component; it modulates structure, assembly, and function of the complex.

"COX6B1 is **not catalytic**; it is a **small, nuclear-encoded accessory subunit** that modulates structure/assembly and function of the complex. "
COX6B1 is positioned on the intermembrane-space (IMS)-facing side of Complex IV at the dimer interface.

"COX6B1 is positioned on the **intermembrane-space (IMS)-facing side** of complex IV. Structural placement from reviews and figure evidence shows COX6B1 exposed on the IMS side and situated at/near the **dimer interface**. "
COX6B1 bridges the two monomers of the COX dimer and supports dimer stability and cooperative function; loss leads to monomerization and ~2-fold increase in enzyme activity without changing proton stoichiometry.

"Experimental removal/loss of COX6B1 (e.g., during mild solubilization) leads to **monomerization** of COX and is associated with a **~two-fold increase in enzyme activity** without changing proton stoichiometry, interpreted as loss of inter-monomer cooperativity and altered cytochrome c binding kinetics. "
Cytochrome c oxidase is the terminal enzyme of the mitochondrial electron transport chain, transferring electrons from cytochrome c to molecular oxygen and contributing to the proton gradient used for ATP synthesis.

"Cytochrome c oxidase (complex IV; COX/CCO) is the terminal enzyme of the mitochondrial electron transport chain. Its catalytic core transfers electrons from cytochrome c to molecular oxygen and contributes to the proton gradient used for ATP synthesis. "
COX6B1 functions within the oxidative phosphorylation pathway as a Complex IV accessory subunit contributing to quaternary structure (dimerization) and assembly/biogenesis.

"COX6B1 functions within the **oxidative phosphorylation** pathway as a complex IV accessory subunit that contributes to **quaternary structure** (dimerization) and is linked to **assembly/biogenesis** of the complex. "
Recent KO/complementation evidence indicates COX6B1 is essential for an early, redox-sensitive step in Complex IV biogenesis, particularly affecting MT-CO2 maturation/metalation with altered copper-delivery/assembly factors (COA6, SCO1, SCO2).

"More recent mechanistic work (preprint) using COX6B1 knockout/complementation in human cells argues COX6B1 is also essential for an **early, redox-sensitive step** in biogenesis—particularly affecting **MT-CO2 maturation/metalation**, with altered abundance/association of copper-delivery/assembly factors (e.g., COA6/SCO1/SCO2). "
Pathogenic homozygous missense variants in a conserved N-terminal arginine (R19/R20) cause infantile/early-onset encephalomyopathy with isolated Complex IV deficiency; severe cases include hydrocephalus and hypertrophic cardiomyopathy.

"Pathogenic **homozygous missense** variants in a conserved arginine in the N-terminus region are repeatedly highlighted. Depending on numbering conventions these appear as **R19H/R19C** or **R20H/R20C**. Reported phenotypes include **infantile/early-onset encephalomyopathy** with isolated complex IV deficiency; more severe presentations include **hydrocephalus** and **hypertrophic cardiomyopathy** (notably with Arg→Cys). "
Patient fibroblasts and muscle with Arg20His show reduced COX6B1 steady-state levels, decreased incorporation into assembling Complex IV, and accumulation of assembly intermediate S3; wild-type COX6B1 complementation restores Complex IV content and activity.

"A 2020 review summarizes evidence that patient fibroblasts and muscle with **Arg20His** show reduced COX6B1 steady-state levels and decreased incorporation into assembling complex IV, with accumulation of assembly intermediate **S3** and selective reduction in complex IV activity (other OXPHOS complexes relatively unaffected). Importantly, **wild-type COX6B1 complementation restores** complex IV content and activity, supporting causality. "
The somatic COX6B1 isoform is distinct from the testis-enriched paralog COX6B2; identity and isoform context are important for interpreting reproductive/cancer studies.

"COX VIb exists as (at least) a broadly expressed somatic isoform (**COX6B1**) and a testis-enriched isoform (**COX6B2**). This matters for interpretation of studies in reproductive tissues and cancers where COX6B2 may be induced. "