ATAD3C is a primate paralog of the mitochondrial AAA+ ATPase ATAD3A that lacks ATAD3A's first ~70 residues. Long regarded as a pseudogene, it is expressed at the protein level. It is an integral mitochondrial membrane protein with its C-terminus in the intermembrane space. It keeps the Walker A and B nucleotide-binding motifs but has a cysteine in place of the AAA+ arginine finger. ATAD3C monomers incorporate into ATAD3A oligomers and reduce their size. Its overexpression lowers respiration and proliferation, raises ROS, and disrupts respiratory supercomplexes, indicating that it acts as a dominant-negative regulator of ATAD3A. Recombination between ATAD3A and ATAD3C creates pathogenic ATAD3A-ATAD3C fusion genes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding (IEA, InterPro AAA domain). ATAD3C keeps intact Walker A (K183) and Walker B (D236/E237) motifs, so nucleotide binding is plausible. Accepted. Reason: [file:human/ATAD3C/ATAD3C-uniprot.txt "FT BINDING 177..184"] [file:human/ATAD3C/ATAD3C-bioinformatics/RESULTS.md "**Walker A and Walker B are intact:** ATAD3A K358 aligns to ATAD3C K183, and ATAD3A D411/E412 align to ATAD3C D236/E237, with identical windows (GPPGTGKTLFAKK; GLLLFVDEADAFL)."] Supporting Evidence: file:human/ATAD3C/ATAD3C-uniprot.txt FT BINDING 177..184 file:human/ATAD3C/ATAD3C-bioinformatics/RESULTS.md **Walker A and Walker B are intact:** ATAD3A K358 aligns to ATAD3C K183, and ATAD3A D411/E412 align to ATAD3C D236/E237, with identical windows (GPPGTGKTLFAKK; GLLLFVDEADAFL). |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrion (IBA). ATAD3C peptides are detected in HEK293T cells. It is an integral membrane protein with its C-terminus in the intermembrane space, and it incorporates into ATAD3A complexes in the mitochondrial membrane. Accepted. Reason: [PMID:38092275 "We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space."] [PMID:38092275 "This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000554019 SUPPORTS TRANSFER ATAD3 family node seeded by ATAD3A, ATAD3B and invertebrate orthologs; consistent with the ATAD3C topology data (PMID:38092275). Supporting Evidence: PMID:38092275 We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. PMID:38092275 This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. |
| GO:0007005 mitochondrion organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mitochondrion organization (IBA). ATAD3C monomers incorporate into ATAD3A complexes and shrink them, and its expression shifts complex III from supercomplexes to free dimers. It thus modulates inner-membrane organization as a dominant-negative regulator of ATAD3A. Kept as non-core, because the effect is through ATAD3A and is shown only by overexpression. Reason: [PMID:38092275 "This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size."] [PMID:38092275 "Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes."] [PMID:38092275 "Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000554019 SUPPORTS TRANSFER ATAD3 family node; ATAD3C is a truncated primate paralog that acts on ATAD3A rather than independently. Supporting Evidence: PMID:38092275 This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. PMID:38092275 Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. PMID:38092275 Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: ATP hydrolysis activity (IEA, InterPro AAA domain). In oligomeric AAA+ ATPases each subunit's ATP site is completed by the arginine finger of its neighbour. ATAD3C keeps its own cis catalytic residues (Walker A K183, Walker B D236/E237), but it has a cysteine (C291) where ATAD3A has its arginine finger (R466). In a mixed ATAD3A/ATAD3C oligomer, an adjacent ATAD3A could still complete ATAD3C's site, but ATAD3C cannot complete its neighbour's. A homo-oligomer of ATAD3C therefore lacks any complete site, and in mixed complexes ATAD3C poisons the site next to it. The equivalent finger substitutions in SPAST abolish its ATPase activity and act dominant-negatively, and the ATAD3A-C fusion carrying this ATAD3C segment is pathogenic. None of the cited sources reports ATPase activity for ATAD3C. The domain-based mapping assumes a complete AAA+ module; over-annotation. Reason: [PMID:32004445 "The equivalent residue is conserved in all multimeric AAA-domain containing ATPases and functions as an arginine finger, a trans-acting residue that binds to the Ξ³-phosphate of ATP in the neighboring monomer."] [file:human/ATAD3C/ATAD3C-bioinformatics/RESULTS.md "**ATAD3A arginine finger R466 aligns to ATAD3C C291.** The window shows no arginine nearby (ATAD3A DWAINDRINEMVH / ATAD3C DWAINACIDVMVH), so the arginine finger is lost, not offset."] [PMID:32004445 "(C) The ATAD3A arginine finger, Arg466 (yellow) which is changed to a cysteine in the ATAD3A-C fusion gene, is overlaid with the SPAST arginine finger (Arg499; orange)."] [PMID:32004445 "These variants have been shown to result in the complete loss of SPAST ATPase activity,19 leading to disease through a dominant-negative mechanism."] [PMID:38092275 "Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell."] Supporting Evidence: PMID:32004445 The equivalent residue is conserved in all multimeric AAA-domain containing ATPases and functions as an arginine finger, a trans-acting residue that binds to the Ξ³-phosphate of ATP in the neighboring monomer. file:human/ATAD3C/ATAD3C-bioinformatics/RESULTS.md **ATAD3A arginine finger R466 aligns to ATAD3C C291.** The window shows no arginine nearby (ATAD3A DWAINDRINEMVH / ATAD3C DWAINACIDVMVH), so the arginine finger is lost, not offset. file:human/ATAD3C/ATAD3C-bioinformatics/RESULTS.md ATAD3C keeps the nucleotide-binding Walker A and B motifs but has lost the trans-acting arginine finger of the AAA+ module, so an ATAD3C subunit cannot complete the ATP site of its neighbour. PMID:32004445 (C) The ATAD3A arginine finger, Arg466 (yellow) which is changed to a cysteine in the ATAD3A-C fusion gene, is overlaid with the SPAST arginine finger (Arg499; orange). PMID:32004445 These variants have been shown to result in the complete loss of SPAST ATPase activity,19 leading to disease through a dominant-negative mechanism. PMID:32004445 The duplications are predicted to maintain the copy-number of ATAD3A and ATAD3C, duplicate ATAD3B, and create a fusion gene, ATAD3A-C, composed of ATAD3A (Uniprot: Q9NVI7-2, residues 1β405) and ATAD3C (Uniprot: Q5T2N8-1, residues 231β411) (Figures 1B and 1C). PMID:38092275 Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell. |
| GO:0031966 mitochondrial membrane | IDA PMID:38092275 "ATAD3C regulates ATAD3A assembly and function in the mitoch... | NEW | Summary: Mitochondrial membrane (NEW, IDA). ATAD3C is an integral membrane protein with its C-terminus in the intermembrane space, and it is incorporated into the ATAD3A complex 'in the mitochondrial membrane'. The abstract does not name which membrane. The inner membrane is likely, given co-assembly with the inner-membrane ATAD3A, but that is an inference, so the parent term is used. Abstract-only source. Reason: [PMID:38092275 "We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space."] [PMID:38092275 "This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size."] Supporting Evidence: PMID:38092275 We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. PMID:38092275 This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. |
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Download this section (compressed HTML)Q: Does knockout of endogenous ATAD3C enlarge ATAD3A oligomers or increase respiratory supercomplex assembly, and is ATAD3C expression regulated to tune ATAD3A activity?
Experiment: Delete ATAD3C in HEK293T cells and measure ATAD3A complex size by BN-PAGE, supercomplex assembly and respiration; test a C291R ATAD3C variant for restored ATPase activity in mixed oligomers.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether endogenous ATAD3C, at its normal expression level, regulates ATAD3A in any tissue is unknown.
OPEN BIOLOGY
What is known: Established: ATAD3C protein is expressed, sits in a mitochondrial membrane (most likely the inner membrane, by co-assembly with ATAD3A), co-assembles with ATAD3A, and lacks the arginine finger (sequence inference). Its overexpression is dominant negative. Not established: any loss-of-function phenotype, regulation of its expression, or whether ATAD3C's own ATP site turns over ATP in mixed oligomers. No MF is asserted: an ATPase-inhibitor or regulator term would need ATAD3A ATPase activity measured with ATAD3C present, and the study reports only complex size, respiration and supercomplex effects.
Provenance (the field's own admissions):
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