GO:0043462 regulation of ATP-dependent activity: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0043462 (regulation of ATP-dependent activity) is a biological_process that modulates the rate of any ATP-hydrolyzing activity, including ATPases, helicases, chromatin remodellers, and ion transporters [1,3,4].
• ATP-dependent chromatin remodellers use ATP hydrolysis to slide, evict, or restructure nucleosomes, and their activity is tightly regulated to control genome accessibility.
• RNA helicases such as DDX41 require regulated ATPase cycles for antiviral innate immune signaling through cGAS-STING [2,4].
• Mitochondrial ATP-dependent proteases like LONP1 are regulated by substrate binding and the proton gradient, linking ATP-dependent activity to proteostasis [5,8].
• Dysregulation of ATP-dependent activities contributes to cancer, neurodegeneration, and mitochondrial disease, making these regulators attractive therapeutic targets [1,5,7].
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect causal roles of ATP-dependent activity regulators [1,4,8].
Description
GO:0043462, regulation of ATP-dependent activity, is a Gene Ontology biological_process defined as any process that modulates the rate of an ATP-dependent activity [1,3]. ATP-dependent activities are executed by a large superfamily of enzymes that couple the free energy of ATP hydrolysis to mechanical work, substrate translocation, or conformational signaling [1,4]. Because these enzymes participate in nearly every cellular process, their rates must be precisely controlled to match physiological demand and to avoid pathological over- or under-activation [3,5].
regulation of ATP-dependent activity At A Glance
| GO ID | GO:0043462 |
|---|---|
| GO term | regulation of ATP-dependent activity |
| Ontology | biological_process |
| Synonym | regulation of adenosinetriphosphatase activity; regulation of ATPase activity |
| Major function | Modulates the rate of ATP-hydrolyzing enzymes, including ATPases, helicases, and chromatin remodellers |
| Definition source | QuickGO definition: Any process that modulates the rate of an ATP-dependent activity |
| Example regulators | Substrate availability, proton gradient, post-translational modifications, protein partners |
| Disease relevance | Cancer, neurodegeneration, mitochondrial disease, innate immune disorders |
What Is GO:0043462?
In practical terms, GO:0043462 describes the regulatory inputs that set the speed of ATP-hydrolyzing enzymes. These inputs can be direct, such as substrate or cofactor availability, or indirect, such as post-translational modifications, protein-protein interactions, or changes in the local environment like the proton gradient [3,5,8]. The term is ontology-agnostic with respect to the specific ATPase, so it covers regulation of chromatin remodellers, helicases, transporters, and proteases alike [1,4].
Why Is regulation of ATP-dependent activity Important in Cell Biology?
Regulation of ATP-dependent activity is central to cellular energy homeostasis and information flow. ATP-dependent chromatin remodellers control gene expression programs by repositioning nucleosomes, and their dysregulation is linked to cancer and developmental disorders. RNA helicases such as DDX41 are required for cGAS-STING activation against DNA viruses, showing that regulated ATPase cycles are essential for innate immunity. Mitochondrial ATP-dependent proteases like LONP1 maintain proteostasis, and their regulation by substrates and the proton gradient is critical for mitochondrial health [5,8]. Thus, understanding GO:0043462 provides mechanistic insight into diverse physiological and pathological states.
• Controls chromatin accessibility and gene expression through regulated ATP-dependent remodellers.
• Enables antiviral innate immune signaling via regulated RNA helicase DDX41.
• Maintains mitochondrial proteostasis through regulated ATP-dependent proteases such as LONP1 [5,8].
• Regulates ion transporters and channels in response to cytoplasmic ATP levels.
• Modulates RNA helicase activity in transcription, splicing, and translation.
• Links energy status to genome regulation and stress responses [1,7].
• Dysregulation is implicated in cancer, neurodegeneration, and mitochondrial disease [1,5,7].
• Provides targets for therapeutic intervention in metabolic and immune disorders [2,8].
What Happens During regulation of ATP-dependent activity?
Substrate and cofactor availability
In simple terms: The enzyme can only work when its fuel and helpers are present.
ATP-dependent enzymes require ATP and often specific cofactors or substrates to cycle. For example, LONP1 ATPase motor function is activated in a substrate-dependent manner, meaning that binding of a protein substrate stimulates its ATP hydrolysis and proteolytic activity. Similarly, cytoplasmic ATP levels regulate ion transporters and channels, providing a direct link between energy status and transport activity.
Conformational cycling and allosteric control
In simple terms: The enzyme changes shape as it burns ATP, and other molecules can lock or unlock these shapes.
ATP binding and hydrolysis drive conformational changes in ATP-dependent enzymes. Chromatin remodellers couple ATP hydrolysis to nucleosome sliding or eviction through a conserved ATPase motor domain. RNA helicases such as DDX41 use ATP-driven conformational changes to unwind RNA and activate downstream signaling [2,4]. Allosteric regulators can stabilize or destabilize these states, thereby modulating the rate of the ATP-dependent activity.
Environmental and gradient-dependent regulation
In simple terms: The cell's internal environment, like acidity or charge, can speed up or slow down these enzymes.
The proton gradient across the mitochondrial inner membrane regulates mitochondrial proteostasis, including the activity of ATP-dependent proteases. Cytoplasmic ATP-dependent regulation of ion transporters and channels is mediated by messengers such as ATP itself, which can directly bind and modulate transporter activity. These examples show that the local environment is a key regulator of ATP-dependent activity.
Post-translational and protein-protein regulation
In simple terms: Chemical tags and partner proteins can switch these enzymes on or off.
Post-translational modifications and interacting proteins can modulate ATP-dependent activities. For instance, the chromatin remodeller Fun30/Smarcad1 regulates mRNA splicing, and its activity is likely coordinated with splicing factors. Multi-omics analysis identified ATF4 as a key regulator of the mitochondrial stress response, which includes ATP-dependent proteases and chaperones. Such regulatory layers ensure that ATP-dependent activities are tuned to cellular needs.
Key Genes Involved in GO:0043462 regulation of ATP-dependent activity
The following genes encode proteins whose ATP-dependent activities are subject to regulation and are widely studied in the context of GO:0043462.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SMARCA4 | ATP-dependent chromatin remodeller | Cancer, gene expression |
| SMARCA2 | ATP-dependent chromatin remodeller | Cancer, development |
| DDX41 | RNA helicase | Innate immunity, cGAS-STING |
| LONP1 | Mitochondrial ATP-dependent protease | Proteostasis, mitochondrial disease |
| ATF4 | Transcription factor regulating stress response | Mitochondrial stress, integrated stress response |
| FUN30 | ATP-dependent chromatin remodeller | mRNA splicing |
| SMARCAD1 | ATP-dependent chromatin remodeller | mRNA splicing, DNA repair |
| ATP1A1 | Na+/K+-ATPase ion transporter | Ion transport, cytoplasmic ATP regulation |
| ABCB1 | ATP-binding cassette transporter | Drug transport, ATP-dependent regulation |
| CFTR | ATP-dependent chloride channel | Ion transport, cystic fibrosis |
| KCNJ11 | ATP-sensitive potassium channel | Insulin secretion, ATP regulation |
| CLPX | ATP-dependent protease | Mitochondrial proteostasis |
| CLPP | ATP-dependent protease | Mitochondrial proteostasis |
| HSPA1A | ATP-dependent chaperone | Protein folding, stress response |
| HSPA9 | Mitochondrial ATP-dependent chaperone | Mitochondrial proteostasis |
| DDX3X | RNA helicase | RNA metabolism, cancer |
| EIF4A1 | RNA helicase | Translation initiation |
How Is regulation of ATP-dependent activity Regulated?
Regulation of ATP-dependent activity occurs at multiple levels. The proton gradient regulates mitochondrial proteostasis by modulating ATP-dependent proteases. Substrate binding directly activates LONP1 ATPase motor function, illustrating substrate-dependent regulation. Cytoplasmic ATP levels and messengers regulate ion transporters and channels. Post-translational modifications and protein partners further tune chromatin remodellers and helicases [1,4]. The integrated stress response, mediated by ATF4, coordinates mitochondrial ATP-dependent activities with cellular stress.
regulation of ATP-dependent activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SMARCA4 | Cancer (e.g., lung adenocarcinoma) | Knockout and point-mutation cell lines |
| DDX41 | Innate immune deficiency | Knockout and knock-in models |
| LONP1 | Mitochondrial disease, neurodegeneration | Knockout and overexpression models |
| ATF4 | Mitochondrial stress response | Knockout and overexpression models |
| CFTR | Cystic fibrosis | Point-mutation knock-in models |
Cancer
ATP-dependent chromatin remodellers such as SMARCA4 are frequently mutated in cancers, leading to altered gene expression programs. Dysregulated ATP-dependent activities can promote oncogenesis by changing chromatin accessibility and transcriptional output.
Neurodegeneration
Mitochondrial ATP-dependent proteases like LONP1 are critical for neuronal proteostasis, and their dysfunction is linked to neurodegenerative diseases [5,8]. Impaired regulation of ATP-dependent activity can lead to protein aggregation and neuronal death.
Innate immune disorders
DDX41 is required for cGAS-STING activation against DNA virus infection, and mutations in DDX41 are associated with immune dysregulation. Regulated ATP-dependent helicase activity is essential for antiviral defense [2,4].
Mitochondrial disease
Disruption of the proton gradient or ATP-dependent proteases leads to mitochondrial proteostasis defects, contributing to mitochondrial disease [5,7]. ATF4 is a key regulator of the mitochondrial stress response, and its dysfunction exacerbates mitochondrial pathology.
From regulation of ATP-dependent activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SMARCA4 alter chromatin accessibility? | SMARCA4 knockout cell line |
| Does a specific DDX41 mutation impair cGAS-STING signaling? | DDX41 point-mutation knock-in |
| Does LONP1 substrate-dependent activation require a specific residue? | LONP1 point-mutation knock-in |
| Does overexpression of ATF4 rescue mitochondrial stress? | ATF4 overexpression cell line |
| Does tagging endogenous SMARCAD1 reveal its splicing function? | SMARCAD1 tagged knock-in |
| Does knockout of CFTR affect ion transport? | CFTR knockout cell line |
How to Study the regulation of ATP-dependent activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Knockout vs wild-type |
| ATAC-seq | Chromatin accessibility | Remodeller perturbation |
| Proteomics | Protein abundance and interactions | ATP-dependent protease substrates |
| ATPase assay | ATP hydrolysis rate | Enzyme regulation [4,8] |
| Live-cell imaging | Dynamic localization and activity | Ion transport and remodelling [3,6] |
| CRISPR screening | Gene essentiality and modifiers | Identify regulators of ATP-dependent activity |
| Ribo-seq | Translation efficiency | Stress response |
| ChIP-seq | Protein-DNA binding | Chromatin remodeller occupancy |
Genomic and transcriptomic profiling
RNA-seq and ATAC-seq can measure changes in gene expression and chromatin accessibility upon perturbation of ATP-dependent regulators [1,6]. These methods help identify downstream pathways controlled by GO:0043462.
Proteomic and interactomic approaches
Mass spectrometry-based proteomics can quantify ATP-dependent protease substrates and interacting partners [5,8]. Multi-omics analysis has identified ATF4 as a key regulator of the mitochondrial stress response.
Biochemical ATPase assays
In vitro ATPase assays measure the rate of ATP hydrolysis by purified enzymes, allowing direct assessment of regulatory inputs such as substrate binding or cofactors [4,8].
Imaging and live-cell reporters
Fluorescent reporters and live-cell imaging can track ATP-dependent processes such as chromatin remodelling and ion transport in real time [3,6].
How CRISPR Can Be Used to Study GO:0043462 regulation of ATP-dependent activity
Knockout
CRISPR knockout of genes encoding ATP-dependent enzymes or their regulators can reveal loss-of-function phenotypes. For example, SMARCA4 knockout alters chromatin accessibility and gene expression. DDX41 knockout impairs cGAS-STING activation.
Point Mutation
Point mutations can dissect catalytic residues or regulatory phosphorylation sites. LONP1 point mutations can test substrate-dependent activation. CFTR point mutations model cystic fibrosis.
Knock-in
Knock-in of tagged or mutant alleles allows tracking of endogenous proteins. Tagged SMARCAD1 knock-in can reveal its role in mRNA splicing. Knock-in of disease-associated mutations in DDX41 can model immune deficiency.
Overexpression
Overexpression of ATP-dependent enzymes or regulators can test gain-of-function effects. ATF4 overexpression can rescue mitochondrial stress phenotypes. Overexpression of LONP1 can enhance proteostasis.
How EDITGENE Supports regulation of ATP-dependent activity Research
Researchers studying regulation of ATP-dependent activity-related genes often need to determine whether a candidate gene is causally involved in a specific pathway or disease. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models for such functional studies.
Contact EDITGENE today to design your custom CRISPR model for regulation of ATP-dependent activity research.
Frequently Asked Questions About regulation of ATP-dependent activity
What is GO:0043462?
GO:0043462 is the Gene Ontology term for regulation of ATP-dependent activity, defined as any process that modulates the rate of an ATP-dependent activity [1,3].
What genes are involved in regulation of ATP-dependent activity?
Key genes include SMARCA4, DDX41, LONP1, ATF4, and FUN30, among others [1,2,6,7,8].
How is ATP-dependent activity regulated?
It is regulated by substrate availability, cofactors, post-translational modifications, protein partners, and environmental factors such as the proton gradient [3,5,8].
What diseases are linked to dysregulated ATP-dependent activity?
Cancer, neurodegeneration, innate immune disorders, and mitochondrial disease are linked to dysregulation of ATP-dependent activities [1,2,5,7].
What is the role of DDX41 in ATP-dependent activity?
DDX41 is an RNA helicase whose regulated ATPase activity is required for cGAS-STING activation against DNA viruses.
How does LONP1 ATPase activity get regulated?
LONP1 ATPase motor function is activated in a substrate-dependent manner, linking substrate binding to ATP hydrolysis.
What methods study regulation of ATP-dependent activity?
Methods include RNA-seq, ATAC-seq, proteomics, ATPase assays, and live-cell imaging [1,4,5,6].
Can CRISPR be used to study ATP-dependent activity?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect these pathways [1,2,8].
What is the role of chromatin remodellers in ATP-dependent activity?
Chromatin remodellers use ATP hydrolysis to slide or evict nucleosomes, and their activity is regulated to control genome accessibility.
How does the proton gradient regulate ATP-dependent activity?
The proton gradient regulates mitochondrial proteostasis by modulating ATP-dependent proteases and chaperones.
Conclusion
GO:0043462 regulation of ATP-dependent activity is a fundamental biological process that controls the rate of ATP-hydrolyzing enzymes across diverse cellular functions. From chromatin remodelling to antiviral immunity and mitochondrial proteostasis, precise regulation is essential for health, and its dysregulation contributes to major diseases [1,2,5,7]. Continued research using advanced CRISPR models and multi-omics approaches will further illuminate these regulatory mechanisms and open new therapeutic avenues.
References
- 1. 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
- 2. Singh RS et al.. 2022. DDX41 is required for cGAS-STING activation against DNA virus infection.. Cell Rep 39(8):110856 PMID: 35613581
- 3. Hilgemann DW. 1997. Cytoplasmic ATP-dependent regulation of ion transporters and channels: mechanisms and messengers.. Annu Rev Physiol 59:193-220 PMID: 9074761
- 4. Donsbach P et al.. 2021. Regulation of RNA helicase activity: principles and examples.. Biol Chem 402(5):529-559 PMID: 33583161
- 5. Patron M et al.. 2022. Regulation of mitochondrial proteostasis by the proton gradient.. EMBO J 41(16):e110476 PMID: 35912435
- 6. Niu Q et al.. 2020. Role of the ATP-dependent chromatin remodeling enzyme Fun30/Smarcad1 in the regulation of mRNA splicing.. Biochem Biophys Res Commun 526(2):453-458 PMID: 32234239
- 7. Quirós PM et al.. 2017. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.. J Cell Biol 216(7):2027-2045 PMID: 28566324
- 8. Mindrebo JT et al.. 2025. Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.. Proc Natl Acad Sci U S A 122(42):e2415153122 PMID: 41091758
