National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM083122
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
F32GM137470
United States
Cystic Fibrosis Foundation
R026-CR11
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
DK065988
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
HL117836
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
HL096458
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
HL071798
United States
Citation
Journal: Mol Biol Cell / Year: 2021 Title: Structural insights into the cause of human primary ciliary dyskinesia. Authors: Yanhe Zhao / Justine Pinskey / Jianfeng Lin / Weining Yin / Patrick R Sears / Leigh A Daniels / Maimoona A Zariwala / Michael R Knowles / Lawrence E Ostrowski / Daniela Nicastro / Abstract: Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Component 4A () can lead to primary ciliary ...Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Component 4A () can lead to primary ciliary dyskinesia (PCD), a life-shortening disease characterized by chronic respiratory tract infections, abnormal organ positioning, and infertility. Despite its importance for human health, the location of RSPH4A in human cilia has not been resolved, and the structural basis of PCD remains elusive. Here, we present the native three-dimensional structure of human respiratory cilia using samples collected noninvasively from a PCD patient. Using cryo-electron tomography (cryo-ET) and subtomogram averaging, we compared the structures of control and cilia, revealing primary defects in two of the three radial spokes (RSs) within the axonemal repeat and secondary (heterogeneous) defects in the central pair complex. Similar to cilia, the radial spoke heads of RS1 and RS2, but not RS3, were missing in cilia. However, cilia also exhibited defects within the arch domains adjacent to the RS1 and RS2 heads, which were not observed with RSPH1 loss. Our results provide insight into the underlying structural basis for PCD and highlight the benefits of applying cryo-ET directly to patient samples for molecular structure determination.
History
Deposition
Oct 20, 2020
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Header (metadata) release
May 5, 2021
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Map release
May 5, 2021
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Update
Jun 9, 2021
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Current status
Jun 9, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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