GO:0060590 ATPase regulator activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0060590 ATPase regulator activity describes any molecular function that binds to and modulates an ATP hydrolysis activity, acting as a rheostat rather than an ATPase itself.
• Regulators can accelerate, inhibit, or redirect ATPases such as AMPK, chromatin remodellers, CFTR, p97/Cdc48, and V-ATPase, coupling energy consumption to specific cellular outputs.
• The term is ontology-distinct from ATPase activity (GO:0016887) and from ATP binding (GO:0005524); annotation requires a physical regulator-ATPase interaction plus a measured change in hydrolysis.
• Dysregulated ATPase regulation underlies metabolic disease, neurodegeneration, cancer, and channelopathies, making these regulators attractive drug targets.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are the primary tools for causal testing of candidate ATPase regulators.
• EDITGENE provides end-to-end CRISPR cell model generation and CRISPR library screening with bioinformatics to dissect ATPase regulatory networks.
Description
GO:0060590 ATPase regulator activity is a molecular function term in the Gene Ontology that captures proteins which bind to an ATPase and modulate its ATP hydrolysis rate. Rather than hydrolysing ATP themselves, these regulators tune the timing, location, and magnitude of energy release, thereby shaping processes as diverse as glucose sensing, chromatin remodelling, lysosomal stress responses, and ion transport. Because ATP hydrolysis is the universal currency of cellular work, even modest changes in regulator abundance or affinity can rewire entire pathways. For researchers, GO:0060590 provides a precise annotation target when a protein's primary biochemical output is the control of another enzyme's ATPase cycle, distinguishing it from direct ATPases and from ATP-binding proteins. Understanding these regulators is therefore central to mechanistic cell biology and to therapeutic strategies that aim to restore or dampen energy-dependent processes in disease.
ATPase regulator activity At A Glance
| GO ID | GO:0060590 |
|---|---|
| GO term | ATPase regulator activity |
| Ontology | molecular_function |
| Synonym | ATP hydrolysis regulator activity |
| Definition | Binds to and modulates the activity of an ATP hydrolysis activity. |
| Major function | Tuning the rate, location, or coupling of ATP hydrolysis by partner ATPases. |
| Representative ATPases regulated | AMPK, chromatin remodellers, CFTR, p97/Cdc48, V-ATPase, SERCA1, Na+/K+-ATPase |
| Direction of regulation | Positive (activator) or negative (inhibitor) modulation of hydrolysis |
| Annotation evidence | Physical interaction plus a measured change in ATPase activity |
What Is GO:0060590?
In our own words, GO:0060590 ATPase regulator activity is the function of a protein or complex that physically binds to an ATP-hydrolysing enzyme and changes its catalytic rate, substrate preference, or coupling efficiency. The regulator is not the ATPase; it is the modulator. This activity is measured as a change in ATP hydrolysis (for example, Pi release or NADH-coupled assays) in the presence versus absence of the regulator, ideally with direct binding evidence.
Why Is ATPase regulator activity Important in Cell Biology?
ATPase regulator activity is important because it determines when and where the cell spends ATP, converting a generic energy currency into specific biological decisions. Regulators of AMPK, chromatin remodellers, CFTR, p97/Cdc48, and V-ATPase control metabolism, gene expression, protein quality control, and membrane transport, so their dysfunction propagates into metabolic, neurodegenerative, and neoplastic phenotypes. Targeting these regulators, rather than the ATPases themselves, offers a route to selective modulation with potentially fewer off-target effects on global energy metabolism.
• Defines a distinct molecular function class separate from ATPase and ATP-binding activities.
• Controls glucose sensing through AMPK regulation by fructose-1,6-bisphosphate and aldolase.
• Governs chromatin accessibility via ATP-dependent remodeller regulators.
• Shapes lysosomal stress responses through the V-ATPase-ATG16L1-LRRK2 axis.
• Modulates ion transport by CFTR and Na+/K+-ATPase, linking to channelopathies and neuronal excitability.
• Regulates muscle calcium handling through SERCA1 modulation by MCARE.
• Impacts mitochondrial homeostasis via p97/Cdc48 regulation.
• Provides candidate drug targets for metabolic disease, neurodegeneration, and cancer.
• Enables synthetic control of energy-dependent pathways in engineered cells.
• Offers a focused annotation axis for functional genomics and CRISPR screens.
What Happens During ATPase regulator activity?
Recognition and binding of the partner ATPase
In simple terms: The regulator first finds and physically attaches to its target ATPase.
Regulation begins with a specific protein-protein interaction between the regulator and the ATPase. For example, aldolase binds AMPK in a glucose-dependent manner to mediate fructose-1,6-bisphosphate sensing, while chromatin remodeller accessory subunits engage the ATPase motor domain to set targeting specificity. The V-ATPase-ATG16L1 axis illustrates how a membrane-embedded ATPase recruits regulatory partners during lysosomal stress. Binding is often regulated by post-translational modifications or metabolite availability, ensuring that modulation occurs only under appropriate conditions.
Conformational coupling to the catalytic cycle
In simple terms: Once bound, the regulator changes the shape or timing of the ATPase cycle.
Regulators can stabilize particular nucleotide states of the ATPase, alter subunit rotation, or change the rate-limiting step of hydrolysis. In chromatin remodellers, accessory subunits and histone modifications tune the coupling between ATP hydrolysis and nucleosome sliding. For CFTR, the molecular basis of ATPase activity involves nucleotide-binding domain dimerization that can be influenced by interacting partners. p97/Cdc48 regulation similarly depends on cofactor-driven conformational transitions that determine substrate processing.
Modulation of hydrolysis rate and coupling
In simple terms: The regulator makes the ATPase work faster, slower, or more efficiently.
The measurable output of GO:0060590 is a change in ATP hydrolysis. MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity, whereas other regulators inhibit hydrolysis to conserve ATP. Na+/K+-ATPase phosphatase activity is subject to regulation that affects ion transport. In AMPK signalling, aldolase acts as a regulator that translates glycolytic flux into changes in AMPK activity. These examples show that both activation and inhibition are within the scope of the term.
Downstream physiological consequences
In simple terms: The change in ATPase speed produces a specific cellular outcome.
Modulation of ATP hydrolysis propagates into pathway-level effects: metabolic reprogramming via AMPK, altered chromatin states via remodellers, lysosomal and mitochondrial quality control via V-ATPase and p97/Cdc48, and ion homeostasis via CFTR, Na+/K+-ATPase, and SERCA1. In C. elegans, CATP-6 regulates GEM-1, linking ATPase regulation to transporter function. These outcomes explain why ATPase regulators are annotated as distinct molecular functions with broad physiological reach.
Key Genes Involved in GO:0060590 ATPase regulator activity
The following genes and proteins represent well-documented ATPase regulators or regulated ATPases that anchor research on GO:0060590.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PRKAA1/PRKAA2 (AMPK) | Energy sensor ATPase regulated by aldolase and FBP | Metabolic disease, glucose sensing |
| ALDOA/ALDOB | Binds AMPK and mediates fructose-1,6-bisphosphate sensing | Glycolysis-AMPK crosstalk |
| SMARCA4/BRG1 | ATPase motor of SWI/SNF chromatin remodeller | Cancer, chromatin regulation |
| SMARCA2/BRM | ATPase motor of SWI/SNF remodeller | Cancer, differentiation |
| CFTR | Chloride channel with ATPase activity modulated by partners | Cystic fibrosis, channelopathy |
| VPS34/PIK3C3 | Kinase in V-ATPase-ATG16L1 axis context | Lysosomal stress, autophagy |
| LRRK2 | Recruited via V-ATPase-ATG16L1 axis | Parkinson's disease |
| ATG16L1 | Axis component linking V-ATPase to LRRK2 | Autophagy, Crohn's disease |
| ATP13A2/PARK9 | P-type ATPase regulated by CATP-6 ortholog | Neurodegeneration |
| GEM-1 | SLC16A transporter regulated by CATP-6 | Transporter biology |
| ATP2A1 (SERCA1) | Calcium pump ATPase enhanced by MCARE | Muscle physiology |
| MCARE | Enhances SERCA1 activity in fast-twitch muscle | Calcium handling, muscle integrity |
| ATP1A1 (Na+/K+-ATPase) | Ion pump ATPase with regulated phosphatase activity | Neuronal excitability |
| VCP/p97 | AAA+ ATPase with multiple cofactor regulators | Mitochondrial homeostasis, neurodegeneration |
| CDC48 | Yeast ortholog of p97 | Protein quality control |
| ATP6V1A | V-ATPase catalytic subunit | Lysosomal function |
| ATP6V0C | V-ATPase proteolipid subunit | Lysosomal stress |
How Is ATPase regulator activity Regulated?
ATPase regulator activity is itself regulated at multiple levels. Metabolite availability controls regulator binding, as shown for fructose-1,6-bisphosphate and aldolase acting on AMPK. Post-translational modifications and cofactor exchange tune chromatin remodeller ATPase cycles. Cellular stress pathways recruit regulators to specific ATPases, exemplified by the V-ATPase-ATG16L1 axis that recruits LRRK2 during lysosomal stress. In muscle, MCARE availability determines SERCA1 enhancement, and p97/Cdc48 cofactor switching dictates mitochondrial homeostasis. These layers ensure that ATP hydrolysis is matched to physiological demand.
ATPase regulator activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LRRK2 | Parkinson's disease, lysosomal stress | Knock-in of risk variant; KO in iPSC-derived neurons |
| CFTR | Cystic fibrosis | Point-mutation knock-in; overexpression of regulatory partners |
| SMARCA4 | Cancer, chromatin remodelling | KO and point-mutation in cancer cell lines |
| ATP2A1/SERCA1 | Muscle calcium handling disorders | MCARE overexpression and KO in myotubes |
| VCP/p97 | Neurodegeneration, mitochondrial homeostasis | Knock-in of disease mutations; KO in neuronal models |
Metabolic disease and AMPK regulation
Because aldolase and fructose-1,6-bisphosphate regulate AMPK, perturbations in this ATPase regulator axis can alter glucose sensing and energy balance, implicating GO:0060590 in metabolic disorders.
Neurodegeneration and lysosomal/mitochondrial ATPases
The V-ATPase-ATG16L1 axis recruits LRRK2 during lysosomal stress, linking ATPase regulation to Parkinson's disease biology. p97/Cdc48 regulators are likewise central to mitochondrial homeostasis and neurodegeneration, and CATP-6/ATP13A2 orthologs connect ATPase regulation to transporter function in model organisms.
Cancer and chromatin remodeller ATPases
ATP-dependent chromatin remodellers are frequently mutated in cancer, and their regulatory subunits determine which genomic regions are made accessible. Modulating remodeller ATPase activity through its regulators is therefore a candidate therapeutic strategy.
Channelopathies and muscle disease
CFTR ATPase regulation is directly relevant to cystic fibrosis, Na+/K+-ATPase regulation affects neuronal excitability, and MCARE-dependent SERCA1 enhancement is required for muscle calcium handling and integrity.
From ATPase regulator activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is the candidate a bona fide ATPase regulator? | Knockout with rescue by wild-type vs. binding-deficient mutant |
| Does a disease variant alter ATPase modulation? | Point-mutation knock-in of the variant |
| Can a regulator be tagged for interaction studies? | Tagged knock-in (e.g., GFP, HA, BioID) |
| Does overexpression phenocopy pathway activation? | Doxycycline-inducible overexpression |
| Which regulators act in a given cell type? | CRISPR library screening with ATPase activity readout |
| What are the downstream transcriptional consequences? | KO plus RNA-seq and bioinformatics |
How to Study the ATPase regulator activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| NADH-coupled ATPase assay | Rate of ATP hydrolysis | Validating activator or inhibitor regulators |
| Pi release assay | Inorganic phosphate production | Quantifying modulation of CFTR or SERCA1 |
| Co-immunoprecipitation | Physical regulator-ATPase interaction | Confirming binding for GO:0060590 annotation |
| BioID/proximity labelling | Endogenous interactome | Discovering new regulators of p97/Cdc48 or remodellers |
| CRISPR knockout screen | Gene requirement for ATPase output | Identifying regulators in a pathway |
| Live-cell imaging | Localization and dynamics | Linking regulation to lysosomal or muscle phenotypes |
| RNA-seq | Transcriptional consequences | Downstream effects of regulator loss |
| Phosphoproteomics | Signalling changes | Mapping AMPK-related regulatory networks |
Biochemical ATPase assays
Direct measurement of ATP hydrolysis (Pi release, NADH-coupled, or luminescence) in the presence and absence of candidate regulators is the gold-standard assay for GO:0060590. These assays can be coupled to binding studies to confirm physical interaction.
Interaction proteomics
Affinity purification, BioID, and proximity labelling identify regulator-ATPase complexes. Tagged knock-in lines enable endogenous-complex capture, as illustrated by studies of chromatin remodellers and p97/Cdc48 cofactors.
Functional genomics and CRISPR screens
Pooled CRISPR knockout or activation screens with ATPase-dependent reporters reveal which genes modulate hydrolysis in a given context. Hits can be validated individually with the models described below.
Imaging and physiological readouts
Live-cell imaging of ATPase localization, calcium handling, or lysosomal function links molecular regulation to cellular phenotypes, as shown for SERCA1 regulation in muscle and V-ATPase-dependent lysosomal stress responses.
How CRISPR Can Be Used to Study GO:0060590 ATPase regulator activity
Knockout
CRISPR knockout of a candidate regulator is the first test of necessity. Loss of the regulator should change ATPase activity or downstream phenotypes, as demonstrated for chromatin remodeller subunits and p97/Cdc48 cofactors. Rescue with wild-type but not binding-deficient alleles confirms specificity.
Point Mutation
Point-mutation knock-in allows precise testing of residues required for ATPase binding or modulation, and of disease-associated variants. This approach is valuable for CFTR and LRRK2 variants where single amino-acid changes alter regulation.
Knock-in
Tagged knock-in (GFP, HA, BioID) enables endogenous interaction and localization studies without overexpression artifacts, supporting rigorous GO:0060590 annotation. Reporter knock-in can also couple ATPase activity to a fluorescent readout.
Overexpression
Inducible overexpression tests sufficiency: does raising regulator levels enhance or inhibit ATPase activity and phenocopy pathway activation? This is particularly informative for MCARE-SERCA1 and AMPK-aldolase axes.
How EDITGENE Supports ATPase regulator activity Research
Researchers studying ATPase regulator activity-related genes often need to determine whether a candidate gene is causally involved in modulating a specific ATPase, and CRISPR cell models provide the cleanest route to that answer. EDITGENE supports this workflow from design to validated clones.
Contact EDITGENE today to design your custom CRISPR model for ATPase regulator activity research.
Frequently Asked Questions About ATPase regulator activity
What is ATPase regulator activity?
It is the molecular function defined by GO:0060590, in which a protein binds to and modulates the activity of an ATP hydrolysis activity.
What genes are involved in ATPase regulator activity?
Examples include ALDOA/ALDOB (AMPK regulation), SMARCA4/SMARCA2 (chromatin remodellers), MCARE (SERCA1), and cofactors of p97/Cdc48.
How is ATPase regulator activity different from ATPase activity?
An ATPase hydrolyses ATP directly, while a regulator binds the ATPase and changes its hydrolysis rate without being the catalyst.
Which diseases are linked to ATPase regulator activity?
Parkinson's disease via LRRK2 and V-ATPase, cystic fibrosis via CFTR, cancer via chromatin remodellers, and muscle disorders via SERCA1.
How do you measure ATPase regulator activity?
Use biochemical ATP hydrolysis assays with and without the regulator, combined with binding assays such as co-immunoprecipitation.
Can CRISPR be used to study ATPase regulator activity?
Yes. Knockout, point-mutation, knock-in, and overexpression models test necessity, sufficiency, and variant effects on ATPase regulation.
What is the role of AMPK regulation in glucose sensing?
Aldolase and fructose-1,6-bisphosphate act as regulators that couple glycolytic flux to AMPK activity.
How does the V-ATPase-ATG16L1 axis work?
It recruits LRRK2 during lysosomal stress, illustrating how ATPase regulators coordinate stress responses.
What is MCARE and how does it regulate SERCA1?
MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity.
Why is p97/Cdc48 important in mitochondrial homeostasis?
p97/Cdc48 and its regulatory cofactors govern protein quality control pathways essential for mitochondrial function.
Conclusion
GO:0060590 ATPase regulator activity captures a mechanistically rich and disease-relevant class of molecular functions that tune ATP hydrolysis across metabolism, chromatin, transport, and quality control. Because these regulators determine when and where energy is spent, they are high-value targets for both basic discovery and therapeutic intervention. CRISPR-based cell models and functional genomics provide the most direct route to establishing causality for candidate regulators.
References
- 1. Zhang CS et al.. 2017. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.. Nature 548(7665):112-116 PMID: 28723898
- 2. Eustermann S et al.. 2024. Energy-driven genome regulation by ATP-dependent chromatin remodellers.. Nat Rev Mol Cell Biol 25(4):309-332 PMID: 38081975
- 3. Lambie EJ et al.. 2013. CATP-6, a C. elegans ortholog of ATP13A2 PARK9, positively regulates GEM-1, an SLC16A transporter.. PLoS One 8(10):e77202 PMID: 24130856
- 4. Eguchi T et al.. 2024. The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response.. J Cell Biol 223(3) PMID: 38227290
- 5. Swann AC et al.. 1975. Sodium + potassium-activated ATPase of mammalian brain. Regulation of phosphatase activity.. Biochim Biophys Acta 382(3):437-56 PMID: 164910
- 6. Sasaki T et al.. 2025. MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity.. Nat Commun 17(1):629 PMID: 41372236
- 7. Cheung JC et al.. 2008. Molecular basis for the ATPase activity of CFTR.. Arch Biochem Biophys 476(1):95-100 PMID: 18417076
- 8. Ram J et al.. 2025. The many faces of p97/Cdc48 in mitochondrial homeostasis.. Essays Biochem 69(5) PMID: 41498289
