ATP23 encodes a conserved M76-family metalloprotease homolog associated with mitochondria. The ATP23 family is best characterized as a mitochondrial inner-membrane/intermembrane-space factor for ATP synthase biogenesis: yeast Atp23 processes the mitochondrially encoded Atp6/subunit 6 precursor and also promotes Fo-sector assembly independently of proteolysis. Human ATP23 carries the conserved metalloprotease features and is detected in human mitochondrial proteome datasets, but its direct mammalian substrate and submitochondrial topology remain less fully characterized. Older KUB3/XRCC6BP1 literature describes Ku70 binding, but the strongest functional model for UniProt Q9Y6H3 is mitochondrial ATP synthase assembly and mitochondrial protein processing rather than DNA repair.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0033615
mitochondrial proton-transporting ATP synthase complex assembly
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Conserved ATP23-family biology supports a core role in mitochondrial ATP synthase Fo-sector assembly.
Reason: Accept as core. The strongest mechanistic evidence comes from yeast Atp23, where ATP23 mutants impair Fo assembly and protease-inactive Atp23 still supports functional ATPase assembly, separating the assembly-factor role from proteolytic processing. Human ATP synthase assembly literature establishes the ATP6/ATP8 membrane-domain assembly context, while ATP23-specific human substrate data remain limited.
Supporting Evidence:
PMID:17135290
Atp23p, in addition to its processing activity, must provide another important function in F O assembly
PMID:17135290
Atp23p may, therefore, also be a chaperone, which in conjunction with Atp10p mediates the association of subunit 6 with the subunit 9 ring.
PMID:17135288
Atp23 promotes the association of mature Atp6 with Atp9 oligomers
PMID:29440398
This intermediate provides the template for insertion of ATP6 and ATP8
|
|
GO:0034982
mitochondrial protein processing
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATP23-family proteins process mitochondrial Atp6/subunit 6 in yeast; this supports mitochondrial protein processing while the direct human substrate remains unresolved.
Reason: Accept, with the caveat that the precise human cleavage substrate is not established. Yeast Atp23 removes the N-terminal prepeptide from the mitochondrial ATP synthase subunit 6 precursor, and human ATP23 retains the conserved M76/metalloprotease signature. Because mammalian ATP6 lacks the same yeast presequence, this term should be interpreted as conserved ATP23-family mitochondrial protein-processing biology rather than a demonstrated human ATP6 cleavage event.
Supporting Evidence:
PMID:17135290
Atp23p is a mitochondrial protease that removes the 10-residue-long N-terminal prepeptide of the subunit 6 precursor
PMID:17135288
Atp23 serves as a processing peptidase and mediates the maturation of the mitochondrial-encoded F(O)-subunit Atp6 after its insertion into the inner membrane.
file:human/ATP23/ATP23-uniprot.txt
InterPro; IPR019165; Peptidase_M76_ATP23.
|
|
GO:0004222
metalloendopeptidase activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: The metalloendopeptidase activity annotation is supported by the conserved M76 domain and yeast ATP23 active-site evidence.
Reason: Accept as core molecular function. Human ATP23 has the Peptidase_M76_ATP23 InterPro/Pfam signatures and conserved metal-binding/catalytic features; yeast mutagenesis shows that the HEXXH active-site glutamate is required for cleavage of the Atp6 precursor.
Supporting Evidence:
PMID:17135290
It has an HEXXH motif previously shown to be part of the active sites of metalloproteases including zinc proteases
PMID:17135290
Substitution of the essential glutamic acid by glutamine prevents cleavage of the N-terminal prepeptide
file:human/ATP23/ATP23-uniprot.txt
InterPro; IPR019165; Peptidase_M76_ATP23.
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: The generic binary-interactome protein-binding annotation is true at most as high-throughput interaction context and is not informative for ATP23 function.
Reason: Mark as over-annotated. The source is a broad human binary interactome map rather than ATP23-focused functional evidence. For ATP23, the informative molecular function is metalloendopeptidase activity and the informative process is ATP synthase assembly/protein processing; generic protein binding should not be treated as a core function.
Supporting Evidence:
PMID:32296183
To map the reference interactome, we performed nine screens of Space III, followed by pairwise verification by quadruplicate retesting and sequence confirmation.
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
|
|
GO:0005515
protein binding
|
IPI
PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... |
MARK AS OVER ANNOTATED |
Summary: The neurodegenerative-disease interactome annotation is too generic and not a mechanistic ATP23 molecular-function term.
Reason: Mark as over-annotated. The publication reports systematic interaction mapping and aggregation network resources, not a specific ATP23 activity. The ATP23 review should emphasize metalloendopeptidase/ATP synthase assembly biology rather than the uninformative parent term protein binding.
Supporting Evidence:
PMID:32814053
Interactome maps are valuable resources to elucidate protein function and disease mechanisms.
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
KEEP AS NON CORE |
Summary: Cytosol is a broad HPA location and should not define ATP23's core cellular site.
Reason: Keep as non-core. HPA-derived cytosol staining may reflect a non-mitochondrial pool or precursor/background signal, but the coherent ATP23-family model and independent mitochondrial proteome evidence point to mitochondrial localization as the functional location.
Supporting Evidence:
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0005829; C:cytosol; IDA:HPA.
PMID:34800366
We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes
|
|
GO:0005886
plasma membrane
|
IDA
GO_REF:0000052 |
REMOVE |
Summary: Plasma membrane localization is not supported by ATP23's conserved mitochondrial protease/assembly-factor biology.
Reason: Remove. This HPA-derived cellular-component annotation conflicts with stronger ATP23-family and mitochondrial proteome evidence, and there is no functional literature placing ATP23 at the plasma membrane.
Supporting Evidence:
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0005886; C:plasma membrane; IDA:HPA.
PMID:34800366
We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes
PMID:17135290
Atp23p is associated with the mitochondrial inner membrane and is conserved from yeast to humans.
|
|
GO:0030054
cell junction
|
IDA
GO_REF:0000052 |
REMOVE |
Summary: Cell junction localization is not supported by ATP23's mitochondrial protease/assembly factor evidence.
Reason: Remove. This HPA-derived location is not corroborated by UniProt functional features, ATP23 orthology, or mitochondrial proteome evidence, and it is not connected to any supported ATP23 biological role.
Supporting Evidence:
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0030054; C:cell junction; IDA:HPA.
PMID:34800366
We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes
PMID:17135290
Atp23p is associated with the mitochondrial inner membrane and is conserved from yeast to humans.
|
|
GO:0005739
mitochondrion
|
HTP
PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... |
ACCEPT |
Summary: Mitochondrion is the best-supported broad cellular location for ATP23.
Reason: Accept. The human MitoCoP study defines a high-confidence mitochondrial proteome from multiple proteomics/importomics approaches, and ATP23's protein name, M76 family membership, and yeast ortholog evidence all support mitochondrial localization.
Supporting Evidence:
PMID:34800366
We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0005739; C:mitochondrion; HTP:FlyBase.
PMID:17135290
Atp23p is associated with the mitochondrial inner membrane and is conserved from yeast to humans.
PMID:17135288
conserved metallopeptidase present in the intermembrane space, termed Atp23
|
|
GO:0004677
DNA-dependent protein kinase activity
|
TAS
PMID:10219089 Isolation of Ku70-binding proteins (KUBs). |
REMOVE |
Summary: The Ku70-binding paper does not show ATP23/KUB3 has DNA-dependent protein kinase activity.
Reason: Remove. The original publication describes DNA-PK as a separate repair kinase and reports isolation of Ku70-binding proteins, including KUB3. It does not establish KUB3/ATP23 as the catalytic DNA-dependent protein kinase, and this annotation conflicts with the supported metalloprotease/mitochondrial assembly model.
Supporting Evidence:
PMID:10219089
We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses.
PMID:10219089
The role of apoJ/XIP8 in ionizing radiation resistance/sensitivity is under investigation.
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
|
|
GO:0005958
DNA-dependent protein kinase-DNA ligase 4 complex
|
NAS
PMID:10219089 Isolation of Ku70-binding proteins (KUBs). |
REMOVE |
Summary: Ku70 binding does not demonstrate ATP23/KUB3 membership in a DNA-PK-DNA ligase IV complex.
Reason: Remove. The cited abstract indicates that KUB3 interacts with Ku70, but does not place KUB3 in the DNA-PK-DNA ligase IV complex. The assignment appears to over-interpret an alias-linked interaction report and is not part of the conserved ATP23 mitochondrial function.
Supporting Evidence:
PMID:10219089
We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses.
PMID:10219089
KUB3 with Ku70 were confirmed by co-immunoprecipitation analyses
file:human/ATP23/ATP23-uniprot.txt
GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
|
|
GO:0006303
double-strand break repair via nonhomologous end joining
|
TAS
PMID:10219089 Isolation of Ku70-binding proteins (KUBs). |
REMOVE |
Summary: The original KUB3/Ku70 paper is insufficient for annotating ATP23 to NHEJ.
Reason: Remove. The paper frames DNA-PK/Ku as NHEJ machinery but reports KUB3 primarily as a Ku70-binding clone; it does not demonstrate that ATP23 is a NHEJ effector. Later Falcon review also flags KUB3/XRCC6BP1 DNA-repair literature as alias-linked and functionally distinct from the better-supported mitochondrial ATP23 model.
Supporting Evidence:
PMID:10219089
We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses.
PMID:10219089
The role of apoJ/XIP8 in ionizing radiation resistance/sensitivity is under investigation.
file:human/ATP23/ATP23-deep-research-falcon.md
Any functional annotation must explicitly separate (i) robust mitochondrial Atp23 ortholog biology from (ii) KUB3/XRCC6BP1 nuclear DNA-repair reports until mapping is confirmed by a source that links these identifiers directly.
|
|
GO:0005758
mitochondrial intermembrane space
|
ISO
PMID:17135288 Prohibitins interact genetically with Atp23, a novel process... |
NEW |
Summary: Add as a conservative PN-supported location candidate, based on ATP23-family intermembrane-space topology evidence.
Reason: Add as a conservative cellular-component annotation. The PN projection places ATP23 in the intermembrane-space-protease bucket and proposes the compartmental term rather than a shared enzymatic/process term. Ortholog evidence supports Atp23 as an intermembrane-space/inner-membrane protein, but this should be treated as sequence-orthology/topology inference for human ATP23 rather than direct human submitochondrial fractionation.
Supporting Evidence:
PMID:17135288
conserved metallopeptidase present in the intermembrane space, termed Atp23
PMID:17135290
Atp23p is associated with the inner membrane in an orientation such that the C-terminus faces the intermembrane space.
file:human/ATP23/ATP23-notes.md
PN projection review: ATP23 is listed in the PN intermembrane-space-protease bucket with candidate GO:0005758; this is acceptable as a conservative, compartmental location only when supported by ATP23 family topology evidence.
|
Q: What is the direct mammalian substrate, if any, for human ATP23 proteolytic activity, given that mammalian ATP6 does not have the same yeast Atp6 N-terminal presequence?
Q: Has endogenous human ATP23 been directly localized by submitochondrial fractionation or protease-protection assays to the intermembrane-space face of the inner membrane?
Q: Should the historical KUB3/XRCC6BP1 Ku70-binding literature remain linked to ATP23 functional annotation, or should DNA-repair GO annotations be retired as alias-driven over-interpretation?
Experiment: Endogenously tag ATP23 in human cells and test submitochondrial localization by mitochondrial fractionation, alkaline extraction, and protease-protection assays with outer- and inner-membrane permeabilization controls.
Hypothesis: Human ATP23 is an inner-membrane/intermembrane-space ATP synthase assembly factor.
Type: subcellular localization/topology assay
Experiment: Generate ATP23 knockout or knockdown human cells and rescue with wild-type and catalytic-site mutant ATP23; assay ATP synthase assembly by BN-PAGE, complex V activity, ATP6/ATP8 stability, and oxidative phosphorylation phenotypes.
Hypothesis: Human ATP23 supports ATP synthase membrane-domain assembly through conserved M76-family catalytic and non-catalytic functions.
Type: loss-of-function and catalytic-mutant rescue
Experiment: Re-test Ku70 interaction and NHEJ phenotypes using sequence-verified ATP23 constructs, endogenous ATP23 perturbation, and rescue variants that distinguish mitochondrial targeting/topology from any nuclear pool.
Hypothesis: The reported KUB3/Ku70 interaction does not define the main ATP23 gene-product function.
Type: interaction and DNA-repair assay
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The UniProt target provided (Q9Y6H3) is described as a βmitochondrial inner membrane protease ATP23 homologβ and is annotated as a member of the peptidase M76 family. In the primary literature retrieved here, the strongest mechanistic characterization of βAtp23/ATP23β is from Saccharomyces cerevisiae, where ATP23 (YNR020c) encodes an M76 metalloprotease acting at the mitochondrial inner membrane with intermembrane-space (IMS) exposure and a role in ATP synthase subunit 6 (Atp6) processing and assembly. (zeng2007themetalloproteaseencoded pages 1-2, zeng2007themetalloproteaseencoded pages 8-9, osman2007prohibitinsinteractgenetically pages 2-3)
However, there is naming ambiguity: a human glioblastoma study uses the name KUB3 and explicitly states βKUB3 also termed XRCC6BP1 (X-ray repair cross-complementation group 6 binding protein 1)β and discusses binding to Ku70 (XRCC6) and effects on DNA double-strand break (DSB) repair. That paper excerpt does not mention ATP23, UniProt Q9Y6H3, ENSG00000166896, mitochondria, or M76 protease features. Therefore, while KUB3/XRCC6BP1 is a documented alias pair in human cancer/DNA-repair literature, the retrieved evidence does not allow a definitive statement that the Ku70-binding/nuclear DSB-repair role refers to the same protein as mitochondrial ATP23 (Q9Y6H3). Any functional annotation must explicitly separate (i) robust mitochondrial Atp23 ortholog biology from (ii) KUB3/XRCC6BP1 nuclear DNA-repair reports until mapping is confirmed by a source that links these identifiers directly. (fischer2013gliomaamplifiedsequencekub3 pages 1-2, fischer2013gliomaamplifiedsequencekub3 pages 2-4)
Atp23 is an M76-family metalloprotease and ATP synthase biogenesis factor. In yeast, ATP23 encodes a metalloprotease with a conserved HEXXH motif typical of metalloprotease active sites and is conserved across eukaryotes (βfrom yeast to humansβ in the yeast studiesβ comparative statements). (zeng2007themetalloproteaseencoded pages 4-6)
A central concept emerging from independent yeast studies is that Atp23 has two separable functions:
1) Proteolytic processing (maturation) of ATP synthase subunit 6 (Atp6) by removing an N-terminal extension after membrane insertion. (zeng2007themetalloproteaseencoded pages 1-2, zeng2007themetalloproteaseencoded pages 8-9)
2) A protease-independent assembly/chaperone-like role that promotes incorporation of Atp6 into the F1Fo-ATP synthase, particularly steps involving association with the Atp9 ring (FO channel formation). Protease-dead mutants can still allow assembly of a functional ATP synthase and restore respiratory growth, implying the assembly role is not simply a consequence of cleavage. (osman2007prohibitinsinteractgenetically pages 6-7, zeng2007themetalloproteaseencoded pages 8-9)
This dual-function model is important for human annotation because it predicts that even if a human ortholog has reduced/altered substrate processing requirements (e.g., differences in ATP6 N-termini across species), an assembly factor function may be retained.
In yeast, Atp23 is localized to the mitochondrial intermembrane space (IMS) and is associated with the inner membrane such that the C-terminus is exposed to the IMS, supported by protease-protection experiments and biochemical extraction behavior. (osman2007prohibitinsinteractgenetically pages 2-3)
This IMS-facing topology is consistent with how Atp23 can access and cleave an N-terminal segment of Atp6 that becomes IMS-accessible after membrane insertion. (osman2007prohibitinsinteractgenetically pages 7-8, zeng2007themetalloproteaseencoded pages 8-9)
Implication for human ATP23 (Q9Y6H3): the most defensible modelβbased on orthologyβis that human ATP23 is an inner-membraneβassociated M76 metalloprotease with an IMS-exposed catalytic region, participating in complex V (ATP synthase) biogenesis/quality control. This is inference, not direct human experimental proof in the retrieved corpus.
Reaction type (ortholog evidence): Atp23 is a metalloprotease that cleaves a peptide bond to remove an N-terminal extension from Atp6 (ATP synthase subunit 6) in yeast. (zeng2007themetalloproteaseencoded pages 1-2, zeng2007themetalloproteaseencoded pages 8-9)
Substrate specificity: The directly supported substrate is the Atp6 precursor N-terminus, where ~10 residues are removed. The mechanistic requirement for the metal-binding motif is supported by mutagenesis (e.g., mutation of the key glutamate within the HEXXH region abolishing processing). (zeng2007themetalloproteaseencoded pages 8-9, zeng2007themetalloproteaseencoded pages 4-6)
Protease-independent activity: Multiple protease-inactive mutants retain the ability to support assembly of a functional F1Fo ATP synthase, underscoring that βsubstrate specificityβ for the processing reaction does not fully define Atp23βs physiological importance. (osman2007prohibitinsinteractgenetically pages 6-7)
Human caveat: The Osman study notes that the human Atp6 lacks the yeast N-terminal extension that is cleaved in yeast, implying that if human ATP23 is enzymatically active as a protease, its native substrate(s) could differ or the cleavage event could be absent/modified in mammals. This again supports prioritizing the assembly/biogenesis function for human annotation unless a human substrate is experimentally identified. (osman2007prohibitinsinteractgenetically pages 6-7)
ATP synthase assembly step: Yeast studies support a role for Atp23 in mediating Atp6 assembly with the Atp9 oligomer/ring during FO channel formation. (osman2007prohibitinsinteractgenetically pages 7-8, zeng2007themetalloproteaseencoded pages 8-9)
Genetic interaction/mitochondrial membrane proteostasis context: Atp23 genetically interacts with prohibitins (PHB1/PHB2). Synthetic sickness/lethality indicates that Atp23 function intersects with inner membrane scaffolding/proteostasis systems important for respiratory function and ATP synthase biogenesis. (osman2007prohibitinsinteractgenetically pages 2-2)
Human context (assembly literature): A PNAS paper on human ATP synthase membrane-domain assembly cites yeast ATP23/Atp23 as an ATP6/ATP8-related assembly factor (contextualizing how ATP6 is handled in yeast). In the excerpt available, it does not provide direct experiments on human ATP23 itself, but it confirms ATP23βs canonical placement among ATP synthase assembly factors in the fieldβs conceptual framework. (he2018assemblyofthe pages 6-6)
A 2024 NPJ Parkinsonβs Disease study tested whether enhancing mitochondrial proteolysis alleviates Ξ±-synuclein toxicity. In a yeast screen using moderate copy-number increases of mitochondrial proteases, Atp23 was among the proteases showing the highest inhibitory effects on Ξ±-synuclein accumulation in mitochondria, and protease copy-number increases (including Atp23) helped rescue growth defects and restore mitochondrial membrane potential in Ξ±-syn-expressing cells. This result expands the functional context of Atp23-family enzymes beyond ATP synthase assembly to broader mitochondrial proteostasis capacity, though the evidence for Atp23 specifically is in yeast. (zhang2024enhancingmitochondrialproteolysis pages 4-5)
OpenTargets aggregates human genetic association evidence for ATP23 (ENSG00000166896) across multiple phenotypes/diseases. In the retrieved OpenTargets output, ATP23 shows association entries (each with 5 evidence items) and moderate overall scores (β0.20β0.30) for traits including SjΓΆgren syndrome, gout, and myasthenia gravis, among others. These are not mechanistic demonstrations of ATP23 function, but they are relevant for prioritizing ATP23 in downstream functional follow-up or variant interpretation workflows. (OpenTargets Search: -ATP23)
The 2024 Ξ±-synuclein study supports a broader therapeutic concept: increasing activity or abundance of specific mitochondrial proteases can reduce mitochondrial Ξ±-synuclein accumulation and improve cellular fitness. While the most emphasized proteases in that paper include NLN and PITRM1 in mammalian contexts (not ATP23), Atp23βs inclusion among top-performing yeast proteases suggests that proteases involved in inner-membrane proteostasis/assembly may contribute to protecting mitochondria from proteotoxic stressβan angle potentially relevant to neurodegeneration research. (zhang2024enhancingmitochondrialproteolysis pages 4-5)
In glioblastoma models, KUB3 (also termed XRCC6BP1) amplification/expression correlates with improved DSB repair after irradiation; knockdown reduces repair efficiency, and the authors discuss Ku70/DNA-PK pathway context. These findings have potential implications for radiation response in tumors. Importantly, this literature does not establish mitochondrial localization or peptidase activity and should not be used alone to annotate mitochondrial ATP23/Q9Y6H3 function without identifier reconciliation. (fischer2013gliomaamplifiedsequencekub3 pages 1-2)
The Atp23 role as an IMS protease required for Atp6 processing during ATP synthase biogenesis is reiterated in a mitochondrial biogenesis/redox review, reflecting a consensus placement of Atp23 among mitochondrial IMS-associated factors supporting complex V maturation. (osman2007prohibitinsinteractgenetically pages 2-3)
| Evidence item (function/localization) | Species/context | Key finding | Experimental basis (brief) | Citation (first author year) | Publication date (month/year) | URL |
|---|---|---|---|---|---|---|
| Dual function in Atp6 processing and ATP synthase assembly | Saccharomyces cerevisiae Atp23; used as orthologous functional evidence for human ATP23/Q9Y6H3 | ATP23 encodes a conserved metalloprotease required to remove the ~10-residue N-terminal presequence from Atp6/subunit 6; protease-dead mutant still supports assembly/respiratory growth, implying a second assembly/chaperone-like role. Atp23 is associated with the inner membrane and its C-terminus faces the IMS. (zeng2007themetalloproteaseencoded pages 1-2, zeng2007themetalloproteaseencoded pages 8-9, zeng2007themetalloproteaseencoded pages 4-6) | Yeast genetics, catalytic-site mutagenesis (E168Q), mitochondrial translation/assembly assays, respiratory growth rescue, biochemical topology/processing analysis | Zeng 2007 | Feb 2007 | https://doi.org/10.1091/mbc.e06-09-0801 |
| IMS localization and separable protease vs chaperone functions | S. cerevisiae Atp23; strongest mechanistic evidence for ATP23-family role | Atp23 localizes to the mitochondrial intermembrane space; protease-protection and alkaline extraction place the HA-tagged C-terminus in the IMS. Protease activity is required for Atp6 maturation, but protease-inactive mutants still allow assembly of functional F1FO-ATP synthase, separating Atp23's processing and chaperone/assembly roles. Genetic interaction with prohibitins links Atp23 to inner-membrane proteostasis/ATP synthase biogenesis. (osman2007prohibitinsinteractgenetically pages 2-2, osman2007prohibitinsinteractgenetically pages 7-8, osman2007prohibitinsinteractgenetically pages 6-7, osman2007prohibitinsinteractgenetically pages 2-3) | Protease protection, alkaline extraction, BN-PAGE, co-immunoprecipitation with Atp6, site-directed mutagenesis, yeast genetic interaction analysis | Osman 2007 | Feb 2007 | https://doi.org/10.1091/mbc.e06-09-0839 |
| Human ATP synthase assembly context | Human mitochondria; ATP23 discussed as yeast assembly factor context rather than directly functionally tested in human cells in the cited excerpt | Human ATP synthase membrane-domain assembly paper cites yeast ATP23/Atp23 as an assembly factor associated with ATP6/ATP8 biogenesis. The excerpt supports relevance of ATP23 to ATP synthase assembly models, but does not provide direct experimental characterization of human ATP23 in that paper excerpt. (he2018assemblyofthe pages 6-6) | Human ATP synthase assembly study with citation-based contextual comparison to yeast ATP23 literature | He 2018 | Feb 2018 | https://doi.org/10.1073/pnas.1722086115 |
| Review statement: IMS protease role in ATP synthase biogenesis | Yeast/human mitochondrial biogenesis review | Review identifies Atp23 as an IMS protease required for processing Atp6 during ATP synthase biogenesis, reinforcing the submitochondrial localization and functional model derived from yeast primary studies. (osman2007prohibitinsinteractgenetically pages 2-3) | Review synthesis of prior mitochondrial biogenesis/protease literature | Geldon 2021 | Sep 2021 | https://doi.org/10.3389/fcell.2021.720656 |
| KUB3/XRCC6BP1 naming and DNA double-strand break repair claim | Human glioblastoma; same symbol/synonym space relevant to ATP23 alias ambiguity | KUB3 is explicitly described as Ku70-binding protein 3 and also termed XRCC6BP1; elevated KUB3 amplification/expression correlated with more efficient DNA double-strand break repair after ionizing radiation, and prior Ku70 binding was noted/confirmed. The paper excerpt does not mention ATP23, ENSG00000166896, or mitochondrial localization, so it should be treated cautiously as alias-linked but functionally distinct literature relative to mitochondrial ATP23 annotation. (fischer2013gliomaamplifiedsequencekub3 pages 2-4, fischer2013gliomaamplifiedsequencekub3 pages 1-2) | Glioma cell expression/amplification analyses, siRNA knockdown, ectopic expression, DSB-repair assays after irradiation, co-immunoprecipitation with Ku70 | Fischer 2013 | May 2013 | https://doi.org/10.3892/ijo.2013.1937 |
| Atp23 in mitochondrial proteolysis screen for Ξ±-synuclein toxicity | Yeast mitochondrial protease overexpression screen | Atp23 was one of the yeast mitochondrial proteases whose increased copy number reduced mitochondrial Ξ±-synuclein accumulation; Atp23 grouped with Cym1, Prd1, and Imp2 among the strongest inhibitors of Ξ±-syn accumulation and helped rescue growth and membrane-potential defects in the yeast model. This is indirect, non-human evidence linking Atp23-family activity to mitochondrial proteostasis. (zhang2024enhancingmitochondrialproteolysis pages 7-9, zhang2024enhancingmitochondrialproteolysis pages 4-5) | Yeast MoBY plasmid overexpression screen, Ξ±-syn spGFP quantification, immunoblotting, growth rescue, membrane-potential assays | Zhang 2024 | Jun 2024 | https://doi.org/10.1038/s41531-024-00733-y |
Table: This table compiles the most relevant evidence for annotating human ATP23/Q9Y6H3, separating direct human alias literature from stronger mechanistic ortholog evidence in yeast. It is useful for clarifying localization, catalytic/assembly roles, and naming ambiguity involving KUB3/XRCC6BP1.
Most defensible functional model for human ATP23/Q9Y6H3 (based on ortholog evidence): a conserved M76 metalloprotease associated with the mitochondrial inner membrane with IMS exposure, functioning in mitochondrial ATP synthase (complex V) biogenesis, including (at least in yeast) proteolytic processing of ATP6/Atp6 and a separable assembly/chaperone-like role promoting incorporation of ATP6/Atp6 into the FO sector. (zeng2007themetalloproteaseencoded pages 8-9, osman2007prohibitinsinteractgenetically pages 2-3)
What remains unresolved in the retrieved corpus: direct experimental confirmation of (i) human ATP23 submitochondrial topology, (ii) native human substrate(s) and cleavage events, and (iii) whether the nuclear DNA-repair literature on KUB3/XRCC6BP1/Ku70 binding is indeed about the same gene product as UniProt Q9Y6H3. (fischer2013gliomaamplifiedsequencekub3 pages 1-2, osman2007prohibitinsinteractgenetically pages 6-7)
References
(zeng2007themetalloproteaseencoded pages 1-2): Xiaomei Zeng, Walter Neupert, and Alexander Tzagoloff. The metalloprotease encoded byatp23has a dual function in processing and assembly of subunit 6 of mitochondrial atpase. Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0801, doi:10.1091/mbc.e06-09-0801. This article has 151 citations and is from a domain leading peer-reviewed journal.
(zeng2007themetalloproteaseencoded pages 8-9): Xiaomei Zeng, Walter Neupert, and Alexander Tzagoloff. The metalloprotease encoded byatp23has a dual function in processing and assembly of subunit 6 of mitochondrial atpase. Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0801, doi:10.1091/mbc.e06-09-0801. This article has 151 citations and is from a domain leading peer-reviewed journal.
(osman2007prohibitinsinteractgenetically pages 2-3): Christof Osman, Claudia Wilmes, Takashi Tatsuta, and Thomas Langer. Prohibitins interact genetically with atp23, a novel processing peptidase and chaperone for the f1fo-atp synthase. Molecular Biology of the Cell, 18:627-635, Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0839, doi:10.1091/mbc.e06-09-0839. This article has 179 citations and is from a domain leading peer-reviewed journal.
(fischer2013gliomaamplifiedsequencekub3 pages 1-2): ULRIKE FISCHER, STEFANIE RHEINHEIMER, ANDREA KREMPLER, MARKUS LΓBRICH, and ECKART MEESE. Glioma-amplified sequence kub3 influences double-strand break repair after ionizing radiation. International Journal of Oncology, 43:50-56, May 2013. URL: https://doi.org/10.3892/ijo.2013.1937, doi:10.3892/ijo.2013.1937. This article has 15 citations and is from a peer-reviewed journal.
(fischer2013gliomaamplifiedsequencekub3 pages 2-4): ULRIKE FISCHER, STEFANIE RHEINHEIMER, ANDREA KREMPLER, MARKUS LΓBRICH, and ECKART MEESE. Glioma-amplified sequence kub3 influences double-strand break repair after ionizing radiation. International Journal of Oncology, 43:50-56, May 2013. URL: https://doi.org/10.3892/ijo.2013.1937, doi:10.3892/ijo.2013.1937. This article has 15 citations and is from a peer-reviewed journal.
(zeng2007themetalloproteaseencoded pages 4-6): Xiaomei Zeng, Walter Neupert, and Alexander Tzagoloff. The metalloprotease encoded byatp23has a dual function in processing and assembly of subunit 6 of mitochondrial atpase. Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0801, doi:10.1091/mbc.e06-09-0801. This article has 151 citations and is from a domain leading peer-reviewed journal.
(osman2007prohibitinsinteractgenetically pages 6-7): Christof Osman, Claudia Wilmes, Takashi Tatsuta, and Thomas Langer. Prohibitins interact genetically with atp23, a novel processing peptidase and chaperone for the f1fo-atp synthase. Molecular Biology of the Cell, 18:627-635, Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0839, doi:10.1091/mbc.e06-09-0839. This article has 179 citations and is from a domain leading peer-reviewed journal.
(osman2007prohibitinsinteractgenetically pages 7-8): Christof Osman, Claudia Wilmes, Takashi Tatsuta, and Thomas Langer. Prohibitins interact genetically with atp23, a novel processing peptidase and chaperone for the f1fo-atp synthase. Molecular Biology of the Cell, 18:627-635, Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0839, doi:10.1091/mbc.e06-09-0839. This article has 179 citations and is from a domain leading peer-reviewed journal.
(osman2007prohibitinsinteractgenetically pages 2-2): Christof Osman, Claudia Wilmes, Takashi Tatsuta, and Thomas Langer. Prohibitins interact genetically with atp23, a novel processing peptidase and chaperone for the f1fo-atp synthase. Molecular Biology of the Cell, 18:627-635, Feb 2007. URL: https://doi.org/10.1091/mbc.e06-09-0839, doi:10.1091/mbc.e06-09-0839. This article has 179 citations and is from a domain leading peer-reviewed journal.
(he2018assemblyofthe pages 6-6): Jiuya He, Holly C. Ford, Joe Carroll, Corsten Douglas, Evvia Gonzales, Shujing Ding, Ian M. Fearnley, and John E. Walker. Assembly of the membrane domain of atp synthase in human mitochondria. Proceedings of the National Academy of Sciences, 115:2988-2993, Feb 2018. URL: https://doi.org/10.1073/pnas.1722086115, doi:10.1073/pnas.1722086115. This article has 269 citations and is from a highest quality peer-reviewed journal.
(zhang2024enhancingmitochondrialproteolysis pages 4-5): Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay, Rong Chen, Sreekumar Ramachandran, Valina L. Dawson, Ted M. Dawson, and Rong Li. Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity. NPJ Parkinson's Disease, Jun 2024. URL: https://doi.org/10.1038/s41531-024-00733-y, doi:10.1038/s41531-024-00733-y. This article has 17 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: -ATP23): Open Targets Query (-ATP23, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(zhang2024enhancingmitochondrialproteolysis pages 7-9): Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay, Rong Chen, Sreekumar Ramachandran, Valina L. Dawson, Ted M. Dawson, and Rong Li. Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity. NPJ Parkinson's Disease, Jun 2024. URL: https://doi.org/10.1038/s41531-024-00733-y, doi:10.1038/s41531-024-00733-y. This article has 17 citations and is from a domain leading peer-reviewed journal.
Review date: 2026-06-03.
Falcon deep research was requested for the Proteostasis PN review. The command just deep-research-falcon human ATP23 --fallback perplexity-lite produced ATP23-deep-research-falcon.md and one Falcon artifact, but the wrapper returned nonzero after a 600 second Falcon timeout and the configured perplexity-lite fallback failed with a Perplexity quota 401. The Falcon file was still usable and was reviewed together with UniProt, GOA, cached publications, PANTHER/InterPro, and the PN projection reports.
Core biology: human ATP23/Q9Y6H3 is a conserved ATP23-family M76 metalloprotease homolog. The best mechanistic evidence is from yeast ATP23/Atp23. Zeng et al. identify a nuclear ATP23 metalloprotease required for mitochondrial ATPase expression: [PMID:17135290 The metalloprotease encoded by ATP23 has a dual function in processing and assembly of subunit 6 of mitochondrial ATPase., "Mutations in ATP23 cause the accumulation of the precursor form of subunit 6 and prevent assembly of F O ."] They further show processing plus a separate assembly role: [PMID:17135290, "Atp23p, in addition to its processing activity, must provide another important function in F O assembly"] and describe the topology as mitochondrial inner membrane with IMS exposure: [PMID:17135290, "Atp23p is associated with the inner membrane in an orientation such that the C-terminus faces the intermembrane space."] Osman et al. independently summarize the dual function as an IMS peptidase/chaperone for ATP synthase: [PMID:17135288 Prohibitins interact genetically with Atp23, a novel processing peptidase and chaperone for the F1Fo-ATP synthase., "conserved metallopeptidase present in the intermembrane space, termed Atp23"] and [PMID:17135288, "Atp23 promotes the association of mature Atp6 with Atp9 oligomers"].
Human evidence is stronger for mitochondrial context than for direct substrate. He et al. define the human ATP synthase membrane-domain assembly pathway and ATP6/ATP8 insertion context: [PMID:29440398 Assembly of the membrane domain of ATP synthase in human mitochondria., "This intermediate provides the template for insertion of ATP6 and ATP8"]. The human MitoCoP study supports ATP23 as part of a high-confidence mitochondrial proteome, but not a specific submitochondrial topology for ATP23: [PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context., "We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes"]. UniProt records the M76 family/domain and InterPro2GO metalloendopeptidase mapping: [file:human/ATP23/ATP23-uniprot.txt, "InterPro; IPR019165; Peptidase_M76_ATP23."].
PN projection review: ATP23 is listed in the PN intermembrane-space-protease bucket with candidate GO:0005758; this is acceptable as a conservative, compartmental location only when supported by ATP23 family topology evidence.
PN projection review: the projected GO:0035694 mitochondrial protein catabolic process should not be propagated for ATP23 in this review, because the strongest evidence supports ATP synthase assembly and Atp6 processing rather than a demonstrated human mitochondrial protein catabolic-process role.
The 2024 alpha-synuclein paper gives indirect yeast proteostasis context, not a direct human ATP23 annotation basis: [PMID:38906862 Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity., "Atp23 proteases showed the highest inhibitory effects on alpha-Syn accumulation in mitochondria"].
The historical KUB3/XRCC6BP1 DNA-repair annotations should be treated cautiously. The original KUB paper describes Ku70-binding proteins and says [PMID:10219089 Isolation of Ku70-binding proteins (KUBs)., "We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses."] It does not establish ATP23/KUB3 as a DNA-dependent protein kinase, a DNA-PK-DNA ligase IV complex member, or an NHEJ effector. Falcon also explicitly cautions that KUB3/XRCC6BP1 DNA-repair literature should be separated from robust mitochondrial Atp23 ortholog biology until identifier/function mapping is confirmed.
Mitochondrial proteostasis|Organelle-specific protein degradation|Intermembrane space protease (group = mapped, GO:0005758 mitochondrial intermembrane space, more_specific_than_existing_goa); parent class ...|Organelle-specific protein degradation = mapped, GO:0035694 mitochondrial protein catabolic process (new_to_goa).This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q9Y6H3
gene_symbol: ATP23
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
ATP23 encodes a conserved M76-family metalloprotease homolog associated with mitochondria.
The ATP23 family is best characterized as a mitochondrial inner-membrane/intermembrane-space
factor for ATP synthase biogenesis: yeast Atp23 processes the mitochondrially encoded
Atp6/subunit 6 precursor and also promotes Fo-sector assembly independently of proteolysis.
Human ATP23 carries the conserved metalloprotease features and is detected in human
mitochondrial proteome datasets, but its direct mammalian substrate and submitochondrial
topology remain less fully characterized. Older KUB3/XRCC6BP1 literature describes Ku70
binding, but the strongest functional model for UniProt Q9Y6H3 is mitochondrial ATP synthase
assembly and mitochondrial protein processing rather than DNA repair.
existing_annotations:
- term:
id: GO:0033615
label: mitochondrial proton-transporting ATP synthase complex assembly
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Conserved ATP23-family biology supports a core role in mitochondrial ATP synthase
Fo-sector assembly.
action: ACCEPT
reason: >-
Accept as core. The strongest mechanistic evidence comes from yeast Atp23, where ATP23
mutants impair Fo assembly and protease-inactive Atp23 still supports functional ATPase
assembly, separating the assembly-factor role from proteolytic processing. Human ATP
synthase assembly literature establishes the ATP6/ATP8 membrane-domain assembly context,
while ATP23-specific human substrate data remain limited.
additional_reference_ids:
- PMID:17135290
- PMID:17135288
- PMID:29440398
- file:human/ATP23/ATP23-deep-research-falcon.md
supported_by:
- &zeng_dual
reference_id: PMID:17135290
supporting_text: Atp23p, in addition to its processing activity, must provide another important
function in F O assembly
- &zeng_chaperone
reference_id: PMID:17135290
supporting_text: Atp23p may, therefore, also be a chaperone, which in conjunction with Atp10p
mediates the association of subunit 6 with the subunit 9 ring.
- &osman_dual
reference_id: PMID:17135288
supporting_text: Atp23 promotes the association of mature Atp6 with Atp9 oligomers
- &he_context
reference_id: PMID:29440398
supporting_text: This intermediate provides the template for insertion of ATP6 and ATP8
- term:
id: GO:0034982
label: mitochondrial protein processing
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: ATP23-family proteins process mitochondrial Atp6/subunit 6 in yeast; this supports
mitochondrial protein processing while the direct human substrate remains unresolved.
action: ACCEPT
reason: >-
Accept, with the caveat that the precise human cleavage substrate is not established. Yeast
Atp23 removes the N-terminal prepeptide from the mitochondrial ATP synthase subunit 6 precursor,
and human ATP23 retains the conserved M76/metalloprotease signature. Because mammalian ATP6
lacks the same yeast presequence, this term should be interpreted as conserved ATP23-family
mitochondrial protein-processing biology rather than a demonstrated human ATP6 cleavage event.
additional_reference_ids:
- PMID:17135290
- PMID:17135288
- file:human/ATP23/ATP23-uniprot.txt
- file:human/ATP23/ATP23-deep-research-falcon.md
supported_by:
- &zeng_processing
reference_id: PMID:17135290
supporting_text: Atp23p is a mitochondrial protease that removes the 10-residue-long N-terminal
prepeptide of the subunit 6 precursor
- &osman_processing
reference_id: PMID:17135288
supporting_text: Atp23 serves as a processing peptidase and mediates the maturation of the
mitochondrial-encoded F(O)-subunit Atp6 after its insertion into the inner membrane.
- &uniprot_m76
reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: InterPro; IPR019165; Peptidase_M76_ATP23.
- term:
id: GO:0004222
label: metalloendopeptidase activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: The metalloendopeptidase activity annotation is supported by the conserved M76 domain
and yeast ATP23 active-site evidence.
action: ACCEPT
reason: >-
Accept as core molecular function. Human ATP23 has the Peptidase_M76_ATP23 InterPro/Pfam
signatures and conserved metal-binding/catalytic features; yeast mutagenesis shows that the
HEXXH active-site glutamate is required for cleavage of the Atp6 precursor.
additional_reference_ids:
- PMID:17135290
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- &zeng_active_site
reference_id: PMID:17135290
supporting_text: It has an HEXXH motif previously shown to be part of the active sites of
metalloproteases including zinc proteases
- &zeng_cleavage
reference_id: PMID:17135290
supporting_text: Substitution of the essential glutamic acid by glutamine prevents cleavage
of the N-terminal prepeptide
- *uniprot_m76
- &uniprot_metallo
reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: The generic binary-interactome protein-binding annotation is true at most as
high-throughput interaction context and is not informative for ATP23 function.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Mark as over-annotated. The source is a broad human binary interactome map rather than
ATP23-focused functional evidence. For ATP23, the informative molecular function is
metalloendopeptidase activity and the informative process is ATP synthase assembly/protein
processing; generic protein binding should not be treated as a core function.
additional_reference_ids:
- PMID:17135290
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- reference_id: PMID:32296183
supporting_text: To map the reference interactome, we performed nine screens of Space III,
followed by pairwise verification by quadruplicate retesting and sequence confirmation.
- *uniprot_metallo
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
qualifier: enables
review:
summary: The neurodegenerative-disease interactome annotation is too generic and not a
mechanistic ATP23 molecular-function term.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Mark as over-annotated. The publication reports systematic interaction mapping and aggregation
network resources, not a specific ATP23 activity. The ATP23 review should emphasize
metalloendopeptidase/ATP synthase assembly biology rather than the uninformative parent term
protein binding.
additional_reference_ids:
- PMID:17135290
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- reference_id: PMID:32814053
supporting_text: Interactome maps are valuable resources to elucidate protein function and
disease mechanisms.
- *uniprot_metallo
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Cytosol is a broad HPA location and should not define ATP23's core cellular site.
action: KEEP_AS_NON_CORE
reason: >-
Keep as non-core. HPA-derived cytosol staining may reflect a non-mitochondrial pool or
precursor/background signal, but the coherent ATP23-family model and independent mitochondrial
proteome evidence point to mitochondrial localization as the functional location.
additional_reference_ids:
- PMID:34800366
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- &uniprot_cytosol
reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: GO; GO:0005829; C:cytosol; IDA:HPA.
- &mitocop
reference_id: PMID:34800366
supporting_text: We defined a human mitochondrial high-confidence proteome (MitoCoP) of
1,134 protein-coding genes
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Plasma membrane localization is not supported by ATP23's conserved mitochondrial
protease/assembly-factor biology.
action: REMOVE
reason: >-
Remove. This HPA-derived cellular-component annotation conflicts with stronger ATP23-family
and mitochondrial proteome evidence, and there is no functional literature placing ATP23 at
the plasma membrane.
additional_reference_ids:
- PMID:34800366
- PMID:17135290
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: GO; GO:0005886; C:plasma membrane; IDA:HPA.
- *mitocop
- &zeng_inner_membrane
reference_id: PMID:17135290
supporting_text: Atp23p is associated with the mitochondrial inner membrane and is conserved
from yeast to humans.
- term:
id: GO:0030054
label: cell junction
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Cell junction localization is not supported by ATP23's mitochondrial protease/assembly
factor evidence.
action: REMOVE
reason: >-
Remove. This HPA-derived location is not corroborated by UniProt functional features, ATP23
orthology, or mitochondrial proteome evidence, and it is not connected to any supported ATP23
biological role.
additional_reference_ids:
- PMID:34800366
- PMID:17135290
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: GO; GO:0030054; C:cell junction; IDA:HPA.
- *mitocop
- *zeng_inner_membrane
- term:
id: GO:0005739
label: mitochondrion
evidence_type: HTP
original_reference_id: PMID:34800366
qualifier: located_in
review:
summary: Mitochondrion is the best-supported broad cellular location for ATP23.
action: ACCEPT
reason: >-
Accept. The human MitoCoP study defines a high-confidence mitochondrial proteome from multiple
proteomics/importomics approaches, and ATP23's protein name, M76 family membership, and yeast
ortholog evidence all support mitochondrial localization.
additional_reference_ids:
- PMID:17135290
- PMID:17135288
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- *mitocop
- &uniprot_mito
reference_id: file:human/ATP23/ATP23-uniprot.txt
supporting_text: GO; GO:0005739; C:mitochondrion; HTP:FlyBase.
- *zeng_inner_membrane
- &osman_ims
reference_id: PMID:17135288
supporting_text: conserved metallopeptidase present in the intermembrane space, termed Atp23
- term:
id: GO:0004677
label: DNA-dependent protein kinase activity
evidence_type: TAS
original_reference_id: PMID:10219089
qualifier: enables
review:
summary: The Ku70-binding paper does not show ATP23/KUB3 has DNA-dependent protein kinase
activity.
action: REMOVE
reason: >-
Remove. The original publication describes DNA-PK as a separate repair kinase and reports
isolation of Ku70-binding proteins, including KUB3. It does not establish KUB3/ATP23 as the
catalytic DNA-dependent protein kinase, and this annotation conflicts with the supported
metalloprotease/mitochondrial assembly model.
additional_reference_ids:
- file:human/ATP23/ATP23-deep-research-falcon.md
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- &kub3_abstract
reference_id: PMID:10219089
supporting_text: We isolated Ku70-binding proteins (KUB1-KUB4) using yeast two-hybrid analyses.
- &kub3_role_under_investigation
reference_id: PMID:10219089
supporting_text: The role of apoJ/XIP8 in ionizing radiation resistance/sensitivity is under
investigation.
- *uniprot_metallo
- term:
id: GO:0005958
label: DNA-dependent protein kinase-DNA ligase 4 complex
evidence_type: NAS
original_reference_id: PMID:10219089
qualifier: part_of
review:
summary: Ku70 binding does not demonstrate ATP23/KUB3 membership in a DNA-PK-DNA ligase IV
complex.
action: REMOVE
reason: >-
Remove. The cited abstract indicates that KUB3 interacts with Ku70, but does not place KUB3
in the DNA-PK-DNA ligase IV complex. The assignment appears to over-interpret an alias-linked
interaction report and is not part of the conserved ATP23 mitochondrial function.
additional_reference_ids:
- file:human/ATP23/ATP23-deep-research-falcon.md
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- *kub3_abstract
- reference_id: PMID:10219089
supporting_text: KUB3 with Ku70 were confirmed by co-immunoprecipitation analyses
- *uniprot_metallo
- term:
id: GO:0006303
label: double-strand break repair via nonhomologous end joining
evidence_type: TAS
original_reference_id: PMID:10219089
qualifier: involved_in
review:
summary: The original KUB3/Ku70 paper is insufficient for annotating ATP23 to NHEJ.
action: REMOVE
reason: >-
Remove. The paper frames DNA-PK/Ku as NHEJ machinery but reports KUB3 primarily as a
Ku70-binding clone; it does not demonstrate that ATP23 is a NHEJ effector. Later Falcon review
also flags KUB3/XRCC6BP1 DNA-repair literature as alias-linked and functionally distinct from
the better-supported mitochondrial ATP23 model.
additional_reference_ids:
- file:human/ATP23/ATP23-deep-research-falcon.md
- file:human/ATP23/ATP23-uniprot.txt
supported_by:
- *kub3_abstract
- *kub3_role_under_investigation
- &falcon_alias_caution
reference_id: file:human/ATP23/ATP23-deep-research-falcon.md
supporting_text: Any functional annotation must explicitly separate (i) robust mitochondrial
Atp23 ortholog biology from (ii) KUB3/XRCC6BP1 nuclear DNA-repair reports until mapping is
confirmed by a source that links these identifiers directly.
- term:
id: GO:0005758
label: mitochondrial intermembrane space
evidence_type: ISO
original_reference_id: PMID:17135288
qualifier: located_in
review:
summary: Add as a conservative PN-supported location candidate, based on ATP23-family
intermembrane-space topology evidence.
action: NEW
reason: >-
Add as a conservative cellular-component annotation. The PN projection places ATP23 in the
intermembrane-space-protease bucket and proposes the compartmental term rather than a shared
enzymatic/process term. Ortholog evidence supports Atp23 as an intermembrane-space/inner-membrane
protein, but this should be treated as sequence-orthology/topology inference for human ATP23
rather than direct human submitochondrial fractionation.
additional_reference_ids:
- PMID:17135290
- file:human/ATP23/ATP23-notes.md
supported_by:
- *osman_ims
- reference_id: PMID:17135290
supporting_text: Atp23p is associated with the inner membrane in an orientation such that the
C-terminus faces the intermembrane space.
- reference_id: file:human/ATP23/ATP23-notes.md
supporting_text: 'PN projection review: ATP23 is listed in the PN intermembrane-space-protease
bucket with candidate GO:0005758; this is acceptable as a conservative, compartmental location
only when supported by ATP23 family topology evidence.'
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: PMID:10219089
title: Isolation of Ku70-binding proteins (KUBs).
findings: []
- id: PMID:17135290
title: The metalloprotease encoded by ATP23 has a dual function in processing and assembly of subunit 6 of mitochondrial ATPase.
findings: []
- id: PMID:17135288
title: Prohibitins interact genetically with Atp23, a novel processing peptidase and chaperone for the F1Fo-ATP synthase.
findings: []
- id: PMID:29440398
title: Assembly of the membrane domain of ATP synthase in human mitochondria.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
- id: PMID:34800366
title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
findings: []
- id: PMID:38906862
title: Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.
findings: []
- id: file:human/ATP23/ATP23-uniprot.txt
title: UniProtKB record for human ATP23
findings: []
- id: file:human/ATP23/ATP23-deep-research-falcon.md
title: Falcon deep research report for ATP23
findings: []
- id: file:human/ATP23/ATP23-notes.md
title: ATP23 PN review notes
findings: []
core_functions:
- molecular_function:
id: GO:0004222
label: metalloendopeptidase activity
description: >-
ATP23 is best represented as a conserved mitochondrial M76 metalloprotease and ATP synthase
assembly factor. Yeast Atp23 cleaves the Atp6/subunit 6 precursor and also promotes Atp6
association with the Atp9 ring independently of proteolysis; human ATP23 is inferred to share
this mitochondrial ATP synthase biogenesis/protein-processing role, although the direct human
substrate and cleavage event remain unresolved.
directly_involved_in:
- id: GO:0033615
label: mitochondrial proton-transporting ATP synthase complex assembly
- id: GO:0034982
label: mitochondrial protein processing
locations:
- id: GO:0005739
label: mitochondrion
- id: GO:0005758
label: mitochondrial intermembrane space
supported_by:
- *zeng_processing
- *zeng_chaperone
- *osman_dual
- *uniprot_m76
- *mitocop
proposed_new_terms: []
suggested_questions:
- question: >-
What is the direct mammalian substrate, if any, for human ATP23 proteolytic activity, given
that mammalian ATP6 does not have the same yeast Atp6 N-terminal presequence?
experts: []
- question: >-
Has endogenous human ATP23 been directly localized by submitochondrial fractionation or
protease-protection assays to the intermembrane-space face of the inner membrane?
experts: []
- question: >-
Should the historical KUB3/XRCC6BP1 Ku70-binding literature remain linked to ATP23 functional
annotation, or should DNA-repair GO annotations be retired as alias-driven over-interpretation?
experts: []
suggested_experiments:
- hypothesis: Human ATP23 is an inner-membrane/intermembrane-space ATP synthase assembly factor.
description: >-
Endogenously tag ATP23 in human cells and test submitochondrial localization by mitochondrial
fractionation, alkaline extraction, and protease-protection assays with outer- and inner-membrane
permeabilization controls.
experiment_type: subcellular localization/topology assay
- hypothesis: Human ATP23 supports ATP synthase membrane-domain assembly through conserved M76-family
catalytic and non-catalytic functions.
description: >-
Generate ATP23 knockout or knockdown human cells and rescue with wild-type and catalytic-site
mutant ATP23; assay ATP synthase assembly by BN-PAGE, complex V activity, ATP6/ATP8 stability,
and oxidative phosphorylation phenotypes.
experiment_type: loss-of-function and catalytic-mutant rescue
- hypothesis: The reported KUB3/Ku70 interaction does not define the main ATP23 gene-product function.
description: >-
Re-test Ku70 interaction and NHEJ phenotypes using sequence-verified ATP23 constructs, endogenous
ATP23 perturbation, and rescue variants that distinguish mitochondrial targeting/topology from any
nuclear pool.
experiment_type: interaction and DNA-repair assay