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

The Skraban-Deardorff intellectual disability syndrome (SKDEAS) is associated with diverse mutations inWDR26, encoding a subunit required to assemble a giant oval-shaped supramolecular CTLH E3 ubiquitin ligase complex and substrate recruitment. Structural modeling of SKDEAS-associated mutations combined with functional assays revealed impaired CTLH E3 complex assembly and interactions, thus providing first mechanistic insights into SKDEAS pathology. Patients with Skraban-Deardorff syndrome (SKDEAS), a neurodevelopmental syndrome associated with a spectrum of developmental and intellectual delays and disabilities, harbor diverse mutations inWDR26, 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.

Source: FEBS Letters - April 5, 2024 Category: Biochemistry Authors: Annette Gross, Judith M üller, Jakub Chrustowicz, Alexander Strasser, Karthik V. Gottemukkala, Dawafuti Sherpa, Brenda A. Schulman, Peter J. Murray, Arno F. Alpi Tags: Research Article Source Type: research