COX11 (human) review notes

UniProtKB:Q9Y6N1 — Cytochrome c oxidase assembly protein COX11, mitochondrial. HGNC:2261. 276 AA precursor.

Deep research note: falcon provider was out of credits (402) at time of review; no -deep-research-falcon.md was generated. Review grounded in the UniProt record, seeded GOA TSV, and cached publications/PMID_*.md.

Core biology (verified)

COX11 is a mitochondrial inner-membrane copper metallochaperone required for
Complex IV (cytochrome c oxidase, CcO/CIV) assembly. It is anchored in the inner
membrane by a single transmembrane helix (TRANSMEM 98–120; residues 76–97 matrix,
121–276 intermembrane space per UniProt topology) with a soluble C-terminal Ig-like
headgroup in the intermembrane space. This headgroup carries the conserved copper-binding
CFCF motif (Cys217/Cys219 in human) plus a third membrane-proximal cysteine (Cys121);
UniProt records Cu(+) BINDING at residues 217 and 219.

Function: COX11 receives Cu(I) from the soluble IMS chaperone COX17 and specifically
and directly delivers/inserts copper into the CuB site of the catalytic subunit MT-CO1
(COX1) during CcO assembly. Stable copper binding requires COX11 dimerization, which is
supported by COX19.

Human COX11 knockout is not fully lethal to CcO assembly (unlike yeast): COX11-KO retains
~15% holo-CIV, hinting at a partial alternative CuB metalation route in metazoans, but Cu
supplementation cannot substitute for COX11.
- PMID:35750769
- PMID:35750769

Localization

Mitochondrion inner membrane; single-pass; intermembrane side. UniProt SUBCELLULAR
LOCATION supported by PubMed:15229189, PubMed:9878253, PubMed:35750769.
- UniProt: "SUBCELLULAR LOCATION: Mitochondrion inner membrane ... Single-pass membrane protein ... Intermembrane side"

Disease

Biallelic COX11 variants cause mitochondrial complex IV deficiency nuclear type 23
(MC4DN23; MIM:620275), infantile-onset encephalopathy. COX11 knockdown lowers
respiration-derived ATP, rescuable by CoQ10.
- PMID:36030551
- PMID:36030551
- PMID:36030551

Interactions (mostly non-core / context)

COX2 and COX19 — during CcO assembly / dimerization support (PMID:35750769).
COA4 (Q9NYJ1) — IntAct, PMID:33961781 (BioPlex high-throughput; bare protein binding).
RANBP2 (P49792) — PMID:34400285; RANBP2 binds COX11, relevant to ADANE. Bare protein binding IPI.
CNNM4/ACDP4 (Q6P4Q7) — Y2H, PMID:15840172; also basis of the intracellular cation-homeostasis IDA.

Annotation decisions summary

Core MF: GO:0016531 copper chaperone activity (ISS) — ACCEPT as core.
GO:0005507 copper ion binding (IEA/InterPro) — ACCEPT (consistent with Cu-binding CFCF motif; broader than 0016531 but correct).
Core BP: GO:0033617 mitochondrial respiratory chain complex IV assembly (IDA + IMP) — ACCEPT.
Core CC: GO:0005743 mitochondrial inner membrane (IBA/IEA/IDA/TAS) — ACCEPT.
GO:0006754 ATP biosynthetic process (IMP, PMID:36030551) — indirect/downstream consequence of CIV deficiency; KEEP_AS_NON_CORE.
GO:0030003 intracellular monoatomic cation homeostasis (IDA, PMID:15840172) — CNNM4 coupling context; KEEP_AS_NON_CORE.
GO:0005739 mitochondrion (HTP + IDA) — ACCEPT (broader localization).
GO:0032991 protein-containing complex (IDA) — uninformative parent; MARK_AS_OVER_ANNOTATED (COX11 homodimer / CIV assembly intermediate is the real complex).
GO:0005515 protein binding IPIs (x3) — bare protein binding, uninformative MF; MARK_AS_OVER_ANNOTATED.