Skraban-Deardorff intellectual disability syndrome-associated mutations in 
WDR26 impair CTLH E3 complex assembly

Gross, Annette; Müller, Judith; Chrustowicz, Jakub; Strasser, Alexander; Gottemukkala, Karthik V.; Sherpa, Dawafuti; Schulman, Brenda A.; Murray, Peter J.; Alpi, Arno F.

doi:10.1002/1873-3468.14866

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Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly

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Gross, Annette
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

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Müller, Judith
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons245081

Chrustowicz, Jakub
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Strasser, Alexander
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

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Gottemukkala, Karthik V.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;
IMPRS-ML: Martinsried, Max Planck Institute of Biochemistry, Max Planck Society;

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Sherpa, Dawafuti
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213292

Schulman, Brenda A.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Murray, Peter J.
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77672

Alpi, Arno F.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Gross, A., Müller, J., Chrustowicz, J., Strasser, A., Gottemukkala, K. V., Sherpa, D., et al. (2024). Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly. FEBS Letters, 598(9), 978-994. doi:10.1002/1873-3468.14866.

Cite as: https://hdl.handle.net/21.11116/0000-000F-3C9E-D

Abstract

Patients with Skraban-Deardorff syndrome (SKDEAS), a neurodevelopmental syndrome associated with a spectrum of developmental and intellectual delays and disabilities, harbor diverse mutations in WDR26, encoding a subunit of the multiprotein CTLH E3 ubiquitin ligase complex. Structural studies revealed that homodimers of WDR26 bridge two core-CTLH E3 complexes to generate giant, hollow oval-shaped supramolecular CTLH E3 assemblies. Additionally, WDR26 mediates CTLH E3 complex binding to subunit YPEL5 and functions as substrate receptor for the transcriptional repressor HBP1. Here, we mapped SKDEAS-associated mutations on a WDR26 structural model and tested their functionality in complementation studies using genetically engineered human cells lacking CTLH E3 supramolecular assemblies. Despite the diversity of mutations, 15 of 16 tested mutants impaired at least one CTLH E3 complex function contributing to complex assembly and interactions, thus providing first mechanistic insights into SKDEAS pathology.