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bioRxiv · 10.1101/2025.09.11.675549

CCDC103-mediated assembly of the R2C complex links RUVBL1-RUVBL2 to Primary Ciliary Dyskinesia

Pal, M.·Munoz Hernandez, H.·Shelley, M.·Kelsall, S.·Roumeliotis, T. I.·Choudhary, J.·Pearl, L.·Wieczorek, M.·Roe, S. M.
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Abstract

Primary ciliary dyskinesia (PCD) is a genetic disorder caused by defective cilia motility, powered by axonemal dynein motors. Assembly of these motors is facilitated by the molecular chaperone HSP90, its co-chaperone RUVBL1-RUVBL2 and adaptor proteins such as CCDC103 (aka DNAAF19). Mutations in CCDC103 identified in PCD patients impair dynein assembly, contributing to the disease pathology. Here, we present the cryo-electron microscopy structure of the human RUVBL1-RUVBL2-CCDC103 complex at 3.2[A] resolution, a chaperone assembly we refer to as R2C. It comprises a hetero-hexameric RUVBL1-RUVBL2 ring bound to three CCDC103 molecules via their RUVBL2-binding domains (RBDs), which have additional functions. Unlike RPAP3 of R2TP, a previously defined co-chaperone of HSP90, CCDC103 lacks a PIH1D1-binding motif and TPR domains, but its flexible N-terminal region regulates RUVBL1-RUVBL2 oligomerisation. Our characterisation of the R2C complex presented here enhances understanding of the intricate protein network involved in Hsp90-mediated assembly of dynein motors and how adaptor mutations contribute to PCD.

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Pal, M., Munoz Hernandez, H., Shelley, M., Kelsall, S., Roumeliotis, T. I., Choudhary, J., Pearl, L., Wieczorek, M., Roe, S. M.. 2025-09-13. CCDC103-mediated assembly of the R2C complex links RUVBL1-RUVBL2 to Primary Ciliary Dyskinesia. https://doi.org/10.1101/2025.09.11.675549

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