DNAAF19-RUVBL1/2 complex recruits multiple adaptors to promote dynein arm assembly.
6 affiliations
- 1Genetics and Genomic Medicine Department, University College London, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
- 2Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Health and Life Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
- 3Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
- 4Department of Paediatric Respiratory Medicine, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Guy's and St Thomas' NHS Foundation Trust, London SW3 6NP, United Kingdom.
- 5Core Facility for Medical Proteomics, University of Tübingen, Tübingen 72076, Germany.
- 6Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen 72076, Germany.
Abstract
Cilia are microtubule-based organelles essential for sensing, motility, and fluid transport. Motile cilia rely on inner and outer dynein arms, large multiprotein motor complexes, for force generation and the characteristic bending motion required for ciliary beating. Before being incorporated into cilia, these dynein arms are preassembled in the cytoplasm by dynein axonemal assembly factors (DNAAFs). Defects in this assembly pathway often cause the inherited genetic condition primary ciliary dyskinesia (PCD), in which the loss of dynein arms impairs ciliary motility. The molecular mechanisms governing the precise and timely assembly of dynein arms by DNAAFs remain elusive. Here, we investigated the role of dynein axonemal assembly factor 19 (DNAAF19), a DNAAF frequently mutated in PCD patients with combined inner and outer dynein arm defects. Using biochemical, structural, and proteomic approaches, we find that DNAAF19 is a monomeric protein that interacts directly with the heterohexamer of RUVBL1 and RUVBL2, a multifunctional cochaperone complex involved in ciliary dynein arm assembly. The recurrent PCD-causing variant p.His154Pro partially destabilizes the interaction of DNAAF19 with RUVBL1-RUVBL2. Moreover, we identify Deleted in Primary Ciliary Dyskinesia forming a cocomplex with RUVBL1/2-DNAAF19 in vivo and in vitro. This indicates similarity to R2TP, the HSP90 cochaperone composed of RUVBL1/2-RPAP3-PIH1D1 that assembles different molecular machineries in cells, and to the RUVBL1/2-SPAG1-PIH1D2 complex associated with ciliary dynein arm assembly and PCD. Our results suggest that DNAAF19 acts as a DNAAF in concert with RUVBL1/2 and its interacting proteins, providing insights into the molecular coordination of dynein arm assembly and cell biology of PCD.
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BibTeX
@article{gomes2026dnaaf19ruvbl12,
title = {{DNAAF19-RUVBL1/2 complex recruits multiple adaptors to promote dynein arm assembly.}},
author = {Mafalda de Almeida Gomes and Emma Wood and Thomas Burgoyne and Franziska Klose and Denisa Batrinu and Karsten Boldt and Glenn Carrington and Yehuda Halfon and Rachel George and G Nasir Khan and Tina Beyer and Hannah M Mitchison and Takashi Ochi},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2612755123},
url = {https://europepmc.org/article/MED/42837447},
note = {CC BY},
}
RIS
TY - JOUR
TI - DNAAF19-RUVBL1/2 complex recruits multiple adaptors to promote dynein arm assembly.
AU - Mafalda de Almeida Gomes
AU - Emma Wood
AU - Thomas Burgoyne
AU - Franziska Klose
AU - Denisa Batrinu
AU - Karsten Boldt
AU - Glenn Carrington
AU - Yehuda Halfon
AU - Rachel George
AU - G Nasir Khan
AU - Tina Beyer
AU - Hannah M Mitchison
AU - Takashi Ochi
PY - 2026
DA - 2026/10/06
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2612755123
UR - https://europepmc.org/article/MED/42837447
AB - Cilia are microtubule-based organelles essential for sensing, motility, and fluid transport. Motile cilia rely on inner and outer dynein arms, large multiprotein motor complexes, for force generation and the characteristic bending motion required for ciliary beating. Before being incorporated into cilia, these dynein arms are preassembled in the cytoplasm by dynein axonemal assembly factors (DNAAFs). Defects in this assembly pathway often cause the inherited genetic condition primary ciliary dyskinesia (PCD), in which the loss of dynein arms impairs ciliary motility. The molecular mechanisms governing the precise and timely assembly of dynein arms by DNAAFs remain elusive. Here, we investigated the role of dynein axonemal assembly factor 19 (DNAAF19), a DNAAF frequently mutated in PCD patients with combined inner and outer dynein arm defects. Using biochemical, structural, and proteomic approaches, we find that DNAAF19 is a monomeric protein that interacts directly with the heterohexamer of RUVBL1 and RUVBL2, a multifunctional cochaperone complex involved in ciliary dynein arm assembly. The recurrent PCD-causing variant p.His154Pro partially destabilizes the interaction of DNAAF19 with RUVBL1-RUVBL2. Moreover, we identify Deleted in Primary Ciliary Dyskinesia forming a cocomplex with RUVBL1/2-DNAAF19 in vivo and in vitro. This indicates similarity to R2TP, the HSP90 cochaperone composed of RUVBL1/2-RPAP3-PIH1D1 that assembles different molecular machineries in cells, and to the RUVBL1/2-SPAG1-PIH1D2 complex associated with ciliary dynein arm assembly and PCD. Our results suggest that DNAAF19 acts as a DNAAF in concert with RUVBL1/2 and its interacting proteins, providing insights into the molecular coordination of dynein arm assembly and cell biology of PCD.
SN - 0027-8424
SN - 1091-6490
ER -