GO:0071987 WD40-repeat domain binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0071987 (WD40-repeat domain binding) is a molecular function defined as binding to a WD40 repeat domain, a ~40-amino-acid motif often ending in a W-D dipeptide that assembles into a WD domain.
• WD40-repeat domain binding is central to scaffolding protein-protein interactions in processes such as ciliogenesis, dynein-dynactin assembly, chromatin targeting, and ubiquitin ligase substrate recruitment.
• Disease links include ciliopathies from WDR44 variants, neurodevelopmental syndromes from FBXW7 mutations, and Crohn disease risk via ATG16L1 WD40 domain signaling.
• WD40-repeat proteins are increasingly pursued as drug targets, with inhibitors and degraders developed for WDR5 and chemical probes for WDR91.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal testing of WD40-repeat domain binding interfaces in human cells.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to study WD40-repeat domain binding in disease and development.
Description
GO:0071987, WD40-repeat domain binding, is a molecular function describing the selective interaction of a protein with a WD40 repeat domain, a short structural motif of approximately 40 amino acids that often terminates in a tryptophan-aspartic acid (W-D) dipeptide and assembles into a WD domain. This binding activity is fundamental to the assembly of multi-protein complexes that control diverse cellular processes, from ciliogenesis initiation to dynein-dynactin complex formation and chromatin regulation. Because WD40-repeat domains lack intrinsic catalytic activity, their biological output depends on binding partners that recognize the domain surface and recruit effectors, making GO:0071987 a key node in interaction networks. Researchers study this term to understand how scaffold proteins organize signaling and trafficking, and to identify therapeutic entry points in cancer and genetic disease. The growing availability of CRISPR models allows precise perturbation of WD40-repeat domain binding interfaces, linking molecular function to phenotype.
WD40-repeat domain binding At A Glance
| GO ID | GO:0071987 |
|---|---|
| GO term | WD40-repeat domain binding |
| Ontology | molecular_function |
| Synonym | beta-transducin repeat domain binding; WD domain binding |
| Definition | Binding to a WD40 repeat domain of a protein; the WD40 repeat is a ~40-amino-acid motif often ending in a W-D dipeptide, and several repeats form a WD domain. |
| Major function | Mediates protein-protein interactions that scaffold and regulate multi-protein complexes. |
| Representative processes | Ciliogenesis initiation, dynein-dynactin assembly, chromatin binding, ubiquitin ligase substrate assembly. |
| Disease relevance | Ciliopathies, neurodevelopmental syndromes, Crohn disease risk, cancer. |
| Therapeutic interest | WD40-repeat proteins are pursued as drug targets with inhibitors and degraders. |
What Is GO:0071987?
WD40-repeat domain binding (GO:0071987) is the molecular function of selectively and non-covalently interacting with a WD40 repeat domain of a protein. The WD40 repeat is a short structural motif of about 40 amino acids, frequently ending in a tryptophan-aspartic acid (W-D) dipeptide; multiple repeats combine to form a WD domain that serves as a protein-protein interaction platform. This function is also known as beta-transducin repeat domain binding or WD domain binding.
Why Is WD40-repeat domain binding Important in Cell Biology?
WD40-repeat domain binding is important because it underlies the assembly and regulation of many essential protein complexes, and its perturbation is directly linked to human disease and to emerging therapeutic strategies. Understanding this molecular function helps explain how scaffold proteins convert binding events into cellular decisions, and it provides a rational basis for designing CRISPR models and small-molecule modulators.
• Controls ciliogenesis initiation through WDR44 WD40-repeat domain interactions.
• Enables dynein-dynactin complex assembly via LIS1 and WD40-repeat binding.
• Supports chromatin binding and CRL4-substrate assembly through RepID WD40 domain interactions.
• Regulates ATG16L1-dependent IL10R signaling, with relevance to Crohn disease.
• Underlies FBXW7 tumor suppressor function, where germline variants cause a neurodevelopmental syndrome.
• Provides a target class for drug discovery, including WDR5 inhibitors and degraders.
• Enables chemical probe development for WDR91 using DNA-encoded libraries and machine learning.
• Serves as a paradigm for studying protein-protein interaction domains in health and disease.
Molecular Mechanism of WD40-repeat domain binding
Recognition of the WD40 repeat surface
In simple terms: A binding partner docks onto the top, bottom, or side of a WD40 domain propeller.
WD40 repeat domains form a propeller-like scaffold that presents multiple interaction surfaces, allowing binding partners to recognize specific repeats or inter-repeat loops. This binding is non-covalent and often involves the W-D dipeptide-containing repeats that define the domain. Structural and biochemical studies of WD40-repeat proteins show that binding specificity arises from sequence variation across repeats rather than from catalysis.
Scaffolding and complex assembly
In simple terms: The WD40 domain acts like a hub that brings several proteins together.
Once a partner binds the WD40-repeat domain, it can recruit additional factors to form functional complexes. For example, LIS1 binding to WD40-repeat domains is required for dynein-dynactin complex assembly, a process essential for microtubule-based transport. Similarly, RepID WD40 domain interactions control chromatin binding and CRL4-substrate assembly, linking WD40-repeat domain binding to ubiquitin ligase function.
Regulation by post-translational modifications and disease variants
In simple terms: Chemical tags or mutations can switch binding on or off.
WD40-repeat domain binding can be modulated by post-translational modifications and by disease-associated variants. Germline variants in FBXW7 impair ubiquitination and cause a neurodevelopmental syndrome, showing that disruption of WD40-repeat domain-dependent interactions has physiological consequences. In ATG16L1, the WD40 domain mediates IL10R signaling that is insensitive to the T300A Crohn disease risk polymorphism, indicating that not all disease variants act through this binding function.
Pharmacological modulation of WD40-repeat domain binding
In simple terms: Drugs can block or degrade proteins that use WD40 domains to bind partners.
WD40-repeat proteins are considered a novel target class, and small molecules have been developed to inhibit or degrade them. WDR5 inhibitors and degraders illustrate how blocking WD40-repeat domain-dependent interactions can affect chromatin regulation. A first-in-class small-molecule ligand for WDR91 was discovered using DNA-encoded chemical library selection followed by machine learning, demonstrating that WD40-repeat domain binding can be targeted chemically.
Key Genes Involved in GO:0071987 WD40-repeat domain binding
The following genes and proteins are representative of WD40-repeat domain binding function and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| WDR44 | WD40-repeat domain protein involved in ciliogenesis initiation | Variants cause a ciliopathy spectrum by impairing ciliogenesis initiation |
| LIS1 (PAFAH1B1) | Regulates dynein-dynactin complex assembly | WD40-repeat domain binding is required for dynein-dynactin assembly |
| WDR5 | Chromatin-associated WD40-repeat protein | Target for inhibitors and degraders in cancer research |
| WDR91 | WD40-repeat protein with ligand discovery | First-in-class small-molecule ligand identified by DNA-encoded library and machine learning |
| FBXW7 | Tumor suppressor with WD40-repeat domain | Germline variants impair ubiquitination and cause neurodevelopmental syndrome |
| RepID (DCAF1-associated) | WD40 domain controls chromatin binding and CRL4-substrate assembly | Molecular double clips within RepID WD40 domain regulate chromatin and CRL4 assembly |
| ATG16L1 | WD40 domain mediates IL10R signaling | T300A Crohn disease risk polymorphism does not affect this signaling |
| DDB1 | CRL4 complex component interacting with WD40 proteins | Relevant to RepID WD40 domain-dependent CRL4-substrate assembly |
| CUL4 | Cullin scaffold in CRL4 ubiquitin ligase | Linked to WD40 domain-mediated substrate assembly |
| Dynein | Microtubule motor | Dynein-dynactin assembly depends on LIS1 and WD40-repeat binding |
| Dynactin | Dynein adaptor complex | Assembly requires LIS1 and WD40-repeat domain interactions |
| IL10R | Interleukin 10 receptor | Signaling depends on ATG16L1 WD40 domain |
| Beta-transducin | Prototype WD40 repeat protein | Synonym for WD40-repeat domain binding reflects beta-transducin repeats |
| WDR5 complex partners | Chromatin regulatory complexes | WD40-repeat domain binding is central to WDR5 function |
| WDR91 partners | Endosomal trafficking | Chemical ligand discovery highlights druggability |
| FBXW7 substrates | Ubiquitination targets | Impaired ubiquitination in disease variants |
| Ciliogenesis factors | Cilia assembly | WDR44 variants impair ciliogenesis initiation |
| CRL4 substrates | Ubiquitin-proteasome targets | RepID WD40 domain controls substrate assembly |
How Is WD40-repeat domain binding Regulated?
WD40-repeat domain binding is regulated at multiple levels, including post-translational modifications and disease-associated mutations that alter interaction surfaces. For example, FBXW7 germline variants impair ubiquitination, indicating that disruption of WD40-repeat domain-dependent binding can deregulate substrate turnover. In ATG16L1, the WD40 domain-dependent IL10R signaling is insensitive to the T300A Crohn disease risk polymorphism, suggesting that this particular binding function is not affected by that variant. Pharmacological regulation is also possible, as WDR5 inhibitors and degraders and WDR91 ligands demonstrate that WD40-repeat domain binding can be modulated by small molecules.
WD40-repeat domain binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| WDR44 | Ciliopathy spectrum | Knock-in of patient variants in ciliogenesis models |
| FBXW7 | Neurodevelopmental syndrome | Point mutation knock-in of germline variants |
| ATG16L1 | Crohn disease risk | Knockout and T300A point mutation in immune cells |
| WDR5 | Cancer | Overexpression and degrader studies in cancer cell lines |
| WDR91 | Endosomal trafficking | Ligand treatment in cells with tagged knock-in |
Ciliopathies and developmental disorders
Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation, directly linking WD40-repeat domain binding to developmental disease. This illustrates how disruption of a single WD40-repeat domain interaction can lead to multisystem phenotypes.
Neurodevelopmental syndromes
Germline variants in the tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome, showing that WD40-repeat domain-dependent substrate recruitment is critical for neural development.
Crohn disease and immune signaling
ATG16L1 WD40 domain-dependent IL10R signaling is insensitive to the T300A Crohn disease risk polymorphism, indicating that this WD40-repeat domain binding function may be preserved in a common disease-risk context.
Cancer and therapeutic targeting
WD40-repeat proteins such as WDR5 are pursued as drug targets, with inhibitors and degraders developed for cancer research. The discovery of a first-in-class small-molecule ligand for WDR91 further supports the druggability of WD40-repeat domain binding.
From WD40-repeat domain binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of WD40-repeat domain binding affect ciliogenesis? | WDR44 knockout and point-mutation knock-in cells |
| How does LIS1 WD40-repeat binding control dynein-dynactin assembly? | LIS1 knockout and tagged knock-in for imaging |
| Can WDR5 be targeted by degraders? | WDR5 overexpression and degrader treatment |
| Is WDR91 ligand binding dependent on WD40 domain? | WDR91 knockout and ligand treatment |
| Do FBXW7 variants impair ubiquitination? | FBXW7 point-mutation knock-in and ubiquitination assays |
| Does ATG16L1 WD40 domain mediate IL10R signaling? | ATG16L1 knockout and T300A knock-in |
How to Study the WD40-repeat domain binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Co-immunoprecipitation | Protein-protein interactions | Detect WD40-repeat domain binding partners |
| Pull-down with WD40 domain | Direct binding | Map interaction interfaces |
| CRISPR knockout | Loss-of-function phenotype | Test gene requirement in ciliogenesis |
| Point-mutation knock-in | Specific residue function | Model disease variants in FBXW7 |
| DNA-encoded library selection | Small-molecule binding | Discover WDR91 ligands |
| Ubiquitination assays | Substrate modification | Assess FBXW7 function |
| IL10R signaling assay | Immune signaling | Test ATG16L1 WD40 domain |
| Dynein-dynactin assembly assay | Complex formation | Study LIS1 WD40 binding |
CRISPR knockout and point-mutation models
CRISPR knockout of WD40-repeat domain-containing genes can reveal loss-of-function phenotypes, while point-mutation knock-in can test specific binding interfaces. For example, WDR44 variants in the WD40-repeat domain impair ciliogenesis initiation, and FBXW7 germline variants impair ubiquitination.
Protein interaction and structural methods
Co-immunoprecipitation, pull-down assays, and structural biology can define WD40-repeat domain binding interfaces. Studies of RepID WD40 domain show molecular double clips that control chromatin binding and CRL4-substrate assembly.
Chemical biology and ligand discovery
DNA-encoded chemical library selection followed by machine learning identified a first-in-class small-molecule ligand for WDR91, demonstrating methods to discover modulators of WD40-repeat domain binding. Inhibitors and degraders for WDR5 provide additional chemical biology tools.
Functional assays for signaling and trafficking
IL10R signaling assays can test ATG16L1 WD40 domain function, and dynein-dynactin assembly assays can test LIS1-dependent binding. These functional readouts link molecular binding to cellular outcomes.
How CRISPR Can Be Used to Study GO:0071987 WD40-repeat domain binding
Knockout
CRISPR knockout of WD40-repeat domain-containing genes such as WDR44 or ATG16L1 can reveal whether the domain is required for ciliogenesis or IL10R signaling. Knockout models are essential for establishing causality in disease-relevant pathways.
Point Mutation
Point-mutation knock-in can model disease-associated variants, such as FBXW7 germline variants that impair ubiquitination, or the ATG16L1 T300A polymorphism that does not affect WD40 domain-dependent IL10R signaling. These models distinguish loss-of-function from neutral variants.
Knock-in
Tagged knock-in of WD40-repeat proteins enables imaging and interaction studies, for example to track LIS1-dependent dynein-dynactin assembly or RepID chromatin binding. Knock-in of patient variants can recreate ciliopathy phenotypes.
Overexpression
Overexpression of WD40-repeat proteins such as WDR5 can be used to test inhibitors and degraders, and to study gain-of-function effects in cancer models. Overexpression of WDR91 can support ligand discovery and validation.
How EDITGENE Supports WD40-repeat domain binding Research
Researchers studying WD40-repeat domain binding-related genes often need to determine whether a candidate gene is causally involved in a phenotype, and CRISPR-based cell models provide a rigorous way to test this. By combining knockout, point-mutation, knock-in, and overexpression strategies, it is possible to dissect the specific contribution of WD40-repeat domain interactions to disease and development.
Contact EDITGENE today to design your custom CRISPR model for WD40-repeat domain binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
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| MYB Knockout HEK293 Cell Line | EDJ-KQ839 | Human | 4602 | Details Get a Quote |
| MAP1S Knockout HEK293 Cell Line | EDJ-KQ14193 | Human | 55201 | Details Get a Quote |
| USP47 Knockout HEK293 Cell Line | EDJ-KQ16083 | Human | 55031 | Details Get a Quote |
| MAP1S Knockout A-549 Cell Line | EDJ-KQ44135 | Human | 55201 | Details Get a Quote |
| MAP1S Knockout HCT 116 Cell Line | EDJ-KQ44136 | Human | 55201 | Details Get a Quote |
| MAP1S Knockout HeLa Cell Line | EDJ-KQ44137 | Human | 55201 | Details Get a Quote |
| MYB Knockout HeLa Cell Line | EDJ-KQ18294 | Human | 4602 | Details Get a Quote |
| MYB Knockout HCT 116 Cell Line | EDJ-KQ19624 | Human | 4602 | Details Get a Quote |
| USP47 Knockout A-549 Cell Line | EDJ-KQ47221 | Human | 55031 | Details Get a Quote |
| USP47 Knockout HCT 116 Cell Line | EDJ-KQ47222 | Human | 55031 | Details Get a Quote |
| USP47 Knockout HeLa Cell Line | EDJ-KQ47223 | Human | 55031 | Details Get a Quote |
| MYB Knockout A-549 Cell Line | EDJ-KQ62422 | Human | 4602 | Details Get a Quote |
| DDB1 Knockout HAP1 Cell Line | EDJ-KQ78110 | Human | 1642 | Details Get a Quote |
| DDB1 Knockout HEK293T Cell Line | EDJ-KQ78142 | Human | 1642 | Details Get a Quote |
Frequently Asked Questions About WD40-repeat domain binding
What is GO:0071987 WD40-repeat domain binding?
GO:0071987 is a molecular function describing binding to a WD40 repeat domain, a ~40-amino-acid motif often ending in a W-D dipeptide that forms a WD domain.
What genes are involved in WD40-repeat domain binding?
Representative genes include WDR44, LIS1, WDR5, WDR91, FBXW7, RepID, and ATG16L1, all linked to WD40-repeat domain-dependent processes.
What diseases are associated with WD40-repeat domain binding?
Ciliopathies, neurodevelopmental syndromes, Crohn disease risk, and cancer have been linked to WD40-repeat domain proteins.
How is WD40-repeat domain binding studied?
Methods include co-immunoprecipitation, pull-down assays, CRISPR knockout and knock-in, ubiquitination assays, and chemical ligand discovery.
Why are WD40-repeat proteins drug targets?
WD40-repeat proteins are considered a novel target class, with inhibitors and degraders developed for WDR5 and ligands for WDR91.
What is the role of WDR44 in ciliogenesis?
WDR44 WD40-repeat domain variants cause a ciliopathy spectrum by impairing ciliogenesis initiation.
How does LIS1 relate to WD40-repeat domain binding?
LIS1 is required for dynein-dynactin complex assembly, a process that depends on WD40-repeat domain interactions.
Does the ATG16L1 T300A variant affect WD40 domain signaling?
ATG16L1 WD40 domain-dependent IL10R signaling is insensitive to the T300A Crohn disease risk polymorphism.
What experimental models are used for WD40-repeat domain research?
CRISPR knockout, point-mutation knock-in, tagged knock-in, and overexpression cell models are commonly used.
Can WD40-repeat domain binding be targeted by small molecules?
Yes, WDR5 inhibitors and degraders and a first-in-class WDR91 ligand demonstrate chemical tractability.
Conclusion
GO:0071987 WD40-repeat domain binding is a central molecular function that scaffolds protein-protein interactions in ciliogenesis, dynein-dynactin assembly, chromatin regulation, and immune signaling. Its disruption is linked to ciliopathies, neurodevelopmental syndromes, and cancer, and its druggability is supported by WDR5 inhibitors and WDR91 ligands. CRISPR-based cell models provide a powerful approach to dissect these interactions and to validate therapeutic hypotheses.
References
- 1. Accogli A et al.. 2024. Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.. Nat Commun 15(1):365 PMID: 38191484
- 2. Schapira M et al.. 2017. WD40 repeat domain proteins: a novel target class?. Nat Rev Drug Discov 16(11):773-786 PMID: 29026209
- 3. Singh K et al.. 2024. Molecular mechanism of dynein-dynactin complex assembly by LIS1.. Science 383(6690):eadk8544 PMID: 38547289
- 4. Gurung R et al.. 2023. Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders.. Cancers (Basel) 15(15) PMID: 37568727
- 5. Ahmad S et al.. 2023. Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning.. J Med Chem 66(23):16051-16061 PMID: 37996079
- 6. Stephenson SEM et al.. 2022. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.. Am J Hum Genet 109(4):601-617 PMID: 35395208
- 7. Kim DK et al.. 2021. Molecular double clips within RepID WD40 domain control chromatin binding and CRL4-substrate assembly.. Biochem Biophys Res Commun 567:208-214 PMID: 34171797
- 8. Serramito-Gómez I et al.. 2022. ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism.. Autophagy 18(12):3023-3030 PMID: 35311452
