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bioRxiv · 10.1101/2025.11.05.686565

The Structural Basis of Pacs1-Wdr37 Complex Assembly and Stability

Xiao, L.·Grzemska, M.·Pi, X.·Chen, L.·Turner, M.·Peddada, N.·Calvache, S.·Jia, J.·Beutler, B.·Wu, H.·Nair-Gill, E.
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Abstract

Phosphofurin acidic cluster sorting protein 1 (Pacs1) is a multidomain adaptor proposed to bind transmembrane cargo proteins to facilitate their intracellular trafficking. Pacs1 also forms a complex with WD-repeat protein 37 (Wdr37), which is essential for lymphocyte homeostasis. Despite numerous proposed binding partners, a validated structure for Pacs1-containing protein complexes is lacking. Here, we present the cryo-electron microscopy structure of the Pacs1-Wdr37 complex. Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR), the domain previously linked to cargo recognition. This interaction stabilizes Wdr37 and is critical for the expression of both proteins. A gain-of-function mutation in PACS1 (R203W) causes a highly penetrant neurodevelopmental syndrome. This pathogenic mutation lies on a solvent-exposed surface of the FBR and does not disrupt complex formation. Instead, Pacs1-R203W remains dependent on Wdr37 for stability and its levels can be reduced through targeted Wdr37 proteolytic degradation. Structural homology of the FBR to synaptotagmin C2 domains reveals a previously unrecognized ability of Pacs1 to bind negatively charged phospholipids through a unique positively charged cleft. Together these findings define the structural basis for Pacs1-Wdr37 complex assembly and stability, present potential strategies for Pacs1-mediated neurodevelopmental disease, and suggest novel Pacs1 functions in membrane association.

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Xiao, L., Grzemska, M., Pi, X., Chen, L., Turner, M., Peddada, N., Calvache, S., Jia, J., Beutler, B., Wu, H., Nair-Gill, E.. 2025-11-05. The Structural Basis of Pacs1-Wdr37 Complex Assembly and Stability. https://doi.org/10.1101/2025.11.05.686565

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