Saccharomyces cerevisiae cytochrome oxidase assembly factor 4. 96 aa.
Companion to genes/human/COA4/. Most of the mechanistic genetics for this family is in yeast;
the human review depends on it via cross-species complementation.
Refreshed COA4 from current GOA and UniProt for the IBA campaign. The live GOA
has 18 rows and seeded two new exact-source PMID:20624914 IGI rows that
split the previous aggregate SHY1/CYC1 row into one SHY1 row and one CYC1
row. I accepted both new rows and marked the old aggregate source row
retired: true so the historical assertion stays visible without duplicating
the live exact rows.
The two live PAINT rows are both sound:
PANTHER:PTN004427774 -> GO:0033617 mitochondrial respiratory chain complex
IV assembly, seeded by yeast COA4 target evidence.PANTHER:PTN000341932 -> GO:0005758 mitochondrial intermembrane space,COA4 itself in the WITH/FROM is a target self-seed, not circularity. The
function and localization are experimentally established on the target, and
the PAINT assertions additionally record that these calls are inherited in the
COA4 family.
For PMID:14562095, I left the two genome-wide C-terminal GFP rows asymmetric.
The nuclear row moves to REMOVE as an unsupported compartment for Coa4. The
cytoplasm row moves to MARK_AS_OVER_ANNOTATED rather than REMOVE: cytoplasm
is an entailed parent of mitochondrion/IMS localization, but the Huh et al.
C-terminal GFP row adds no independent evidence for a stable cytoplasmic pool.
CMC2 still needs equivalent follow-up; COX23 is the intentional contrast, where
the Huh cytoplasm row agrees with direct fractionation evidence and can remain
non-core.
The 2024-2026 literature search found no new yeast COA4 primary paper that
changes the 2022/2026 placement of Coa4 upstream of Cox11 in the mitochondrial
copper delivery pathway. PMID:40936169 is a 2025 human cancer paper about COA4
overexpression, and PMID:36101433 was a false-positive PubMed hit.
FUNCTION: Involved in cytochrome c oxidase assembly or stability.SUBCELLULAR LOCATION: Mitochondrion inner membrane. Abundance ~907 molecules/cell.2009 — family survey, as Cmc3 PMID:19703468. Identified among 14 yeast twin Cx9C proteins;
import shown to depend on the Mia40–Erv1 disulfide relay ["which we demonstrated to be dependent
for import"]. Deletion mutants of most family members impair respiratory chain assembly or
stability — the basis of the general GO:0033108 IMP row.
2010 — renaming and characterization PMID:20624914. Isolated as an allele-specific
suppressor of the Shy1 G137E Leigh-syndrome mutant.
- "Coa4 is a twin CX 9 C motif mitochondrial protein localized in the intermembrane space and
associated with the inner membrane"
- "Cells lacking Coa4 are depressed in CcO activity but show no impairment in Cox1 maturation or
formation of the Shy1-stabilized Cox1 assembly intermediate" — places Coa4 downstream of Cox1
synthesis and hemylation.
- "Cells lacking Coa4 resemble shy1 Δ cells in exhibiting a reduced mitochondrial copper content"
- CYC1 (cytochrome c) overexpression restores respiratory function.
- Source of both IGI rows: SGD:S000003344 = SHY1, SGD:S000003809 = CYC1.
2013 — ROS, not assembly, limits growth PMID:23198688. "Deletion of CMC1 or COA4 leads to
assembly defects of cytochrome c oxidase"; DTT/GSH/ascorbate rescue respiratory growth but
"the presence of the reductants does not suppress these assembly defects and the levels of
cytochrome c oxidase remain reduced". Source of the IGI row with SGD:S000001620 = CMC1.
Methodological caveat: respiratory-growth rescue is not evidence of restored assembly.
2012 — IMS proteome PMID:22984289. Bax-release profiling of isolated mitochondria;
"From the known 31 soluble IMS proteins, 29 proteins" were recovered and "we found 20 novel
intermembrane space proteins". Source of the EXP GO:0005758 row. Coa4 is not named in the
cached body text (the assignment is in the study's protein tables), so the SGD curator call is
accepted rather than second-guessed.
2022 — genetic placement in the copper pathway PMID:35666203. Cox11 overexpression restores
Cox1 abundance, CcO assembly and respiration in coa4Δ; the rescue requires Cox11's
copper-coordinating cysteines; Coa4 and Cox11 abundance are reciprocally regulated; coa4Δ has
reduced cellular copper; human COA4 complements coa4Δ. Coa4 is not a metallochaperone —
"Importantly, Coa4 lacks the copper-binding cysteine motif that is found in Cox17, further
negating its metallochaperone role". The authors explicitly could not detect a Coa4–Cox11
physical interaction by co-IP/MS.
2026 — the physical interaction [DOI:10.1038/s41467-026-77112-z]. Co-IP of yeast Coa4-V5 from
DSSO-crosslinked mitochondria recovered Cox11, closing the gap left in 2022 — plausibly because
crosslinking captures a transient contact. Also enriched: "the IMS-localized Ptc5 phosphatase,
which suggests a role for this protein in regulating copper delivery to CcO through reversible
phosphorylation of Coa4 in yeast" — suggestive only, no follow-up.
Core. GO:0033617 mitochondrial respiratory chain complex IV assembly carries IMP evidence
from two independent studies plus three IGI rows (SHY1, CYC1, CMC1). GO:0005758 mitochondrial
intermembrane space carries EXP, two IDA rows, IBA, IEA and TAS. Both are exceptionally
well-supported here — considerably better than in human, which is why the yeast review is the
anchor for the family.
GO:0003674 molecular_function ND. SGD's explicit "no data" placeholder. This is correct
and worth preserving: no catalytic or binding activity has ever been demonstrated for Coa4, and
metallochaperone activity is positively excluded. It independently corroborates the decision in
the human review not to assert a molecular function term.
GO:0033108 mitochondrial respiratory chain complex assembly (IMP, PMID:19703468). Faithful
to that paper, which assayed respiratory chain function generally, but superseded by the
complex IV–specific IMP rows from focused studies. MODIFY → GO:0033617.
GO:0005634 nucleus (HDA, PMID:14562095) — removed. From the genome-wide C-terminal GFP
library. Flagged on conflict grounds, not because the underlying images are unavailable:
- Coa4 is a twin CX9C substrate of the MIA40-ERV1 relay, and there is no described route by which
such a protein reaches the nucleus — import commits it to the IMS, where its disulfides are
oxidatively trapped.
- Contradicted by EXP IMS proteomics, two IDA rows, IBA, IEA, TAS and UniProt, with no other
source of any kind placing Coa4 in the nucleus.
- Most likely a C-terminal GFP fusion that blocked import and was scored outside mitochondria.
Marked REMOVE because all independent sources place Coa4 in the mitochondrion or IMS, and no
source beyond the artifact-prone C-terminal GFP screen supports a nuclear pool.
GO:0005737 cytoplasm (HDA, PMID:14562095) — over-annotated. Deliberately treated
differently from the nucleus row. GO:0005737 is an entailed parent of mitochondrial
localization, so the row is not false in the ontology closure. It is still too broad to
describe Coa4's functional compartment, and its only direct GOA provenance is the same
C-terminal GFP library that likely artifactually inflated the nuclear and cytosolic signal.
GO:0005743 mitochondrial inner membrane (IEA). Consistent with UniProt and with Bestwick's
"associated with the inner membrane", but in slight tension with the Bax-release IMS proteomics
that treats Coa4 as soluble-releasable. Best read as peripheral association; kept non-core.