Structure of the radial spoke head and insights into its role in mechanoregulation of ciliary beating

Grossman-Haham, Iris; Coudray, Nicolas; Yu, Zanlin; Wang, Feng; Zhang, Nan; Bhabha, Gira; Vale, Ronald D.

doi:10.1038/s41594-020-00519-9

Cited by 50 publications

(55 citation statements)

References 67 publications

(132 reference statements)

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“…Our comparative analyses suggest that RPSH4A –/– cilia exhibit more severe RS defects, with the remnant of the stalk structures of RS1 and RS2 appearing shorter than those of RSPH1 –/– cilia in a larger proportion of axonemal repeats ( Figures 2 and 3, G and H ; Supplemental Figure S2; Supplemental Movie S1). These data support a model in which RSPH4A is more centrally located within the RS head than RSPH1, potentially reaching into the arch region or interacting strongly with arch proteins, in agreement with recent findings ( Zheng et al , 2021 ; Grossman-Haham et al. , 2020 ; Gui et al.…”

Section: Discussionsupporting

confidence: 92%

Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Zhao

Pinskey

Lin

et al. 2021

MBoC

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Cilia and flagella are evolutionarily conserved eukaryotic organelles involved in cell motility and signaling. In humans, mutations in Radial Spoke Head Protein 4 homolog A ( RSPH4A) 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 RSPH4A-/- PCD remains elusive. Here, we present the native, three-dimensional structure of RSPH4A-/- human respiratory cilia using samples collected non-invasively from a PCD patient. Using cryo-electron tomography and subtomogram averaging, we compared the structures of control and RSPH4A-/- 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 RSPH1-/- cilia, the radial spoke heads of RS1 and RS2, but not RS3, were missing in RSPH4A-/- cilia. However, RSPH4A-/- 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 RSPH4A-/- PCD and highlight the benefits of applying cryo-ET directly to patient samples for molecular structure determination. [Media: see text]

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Section: Discussionsupporting

confidence: 92%

Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Zhao

Pinskey

Lin

et al. 2021

MBoC

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“…6e ). Interfacing with RS is critical for CPC function 24 , 25 , 27 and extensive contacts between RS and CPC projections are observed in the T. brucei structure (Fig. 6b, f–h ; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of the trypanosome paraflagellar rod and insights into non-planar motility of eukaryotic cells

et al. 2021

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Eukaryotic flagella (synonymous with cilia) rely on a microtubule-based axoneme, together with accessory filaments to carryout motility and signaling functions. While axoneme structures are well characterized, 3D ultrastructure of accessory filaments and their axoneme interface are mostly unknown, presenting a critical gap in understanding structural foundations of eukaryotic flagella. In the flagellum of the protozoan parasite Trypanosoma brucei (T. brucei), the axoneme is accompanied by a paraflagellar rod (PFR) that supports non-planar motility and signaling necessary for disease transmission and pathogenesis. Here, we employed cryogenic electron tomography (cryoET) with sub-tomographic averaging, to obtain structures of the PFR, PFR-axoneme connectors (PACs), and the axonemal central pair complex (CPC). The structures resolve how the 8 nm repeat of the axonemal tubulin dimer interfaces with the 54 nm repeat of the PFR, which consist of proximal, intermediate, and distal zones. In the distal zone, stacked “density scissors” connect with one another to form a “scissors stack network (SSN)” plane oriented 45° to the axoneme axis; and ~370 parallel SSN planes are connected by helix-rich wires into a paracrystalline array with ~90% empty space. Connections from these wires to the intermediate zone, then to overlapping layers of the proximal zone and to the PACs, and ultimately to the CPC, point to a contiguous pathway for signal transmission. Together, our findings provide insights into flagellum-driven, non-planar helical motility of T. brucei and have broad implications ranging from cell motility and tensegrity in biology, to engineering principles in bionics.

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“…Interestingly, the sperm fibrous sheath and ciliary radial spoke complexes are organized by AKAPs and D/D proteins (52,53). Moreover, our exploration of D/D heterodimerization presented in figures 5 and 6 is reminiscent of the recent cryo-EM analyses of the axonemal radial spoke complex (54,55). The radial spoke is a complex of 23 proteins that functions as a mechanochemical transducer that modulates activity of dynein motors to promote flagellar motility.…”

Section: Discussionmentioning

confidence: 92%

Beyond PKA: Evolutionary and structural insights that define a docking and dimerization domain superfamily

Dahlin

Zheng

Scott

2021

Journal of Biological Chemistry

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Structure of the radial spoke head and insights into its role in mechanoregulation of ciliary beating

Cited by 50 publications

References 67 publications

Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Structural insights into the cause of human RSPH4A primary ciliary dyskinesia

Structure of the trypanosome paraflagellar rod and insights into non-planar motility of eukaryotic cells

Beyond PKA: Evolutionary and structural insights that define a docking and dimerization domain superfamily

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