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Cited by 290Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesMicrotubule and mitosis dynamics

Structure of the Decorated Ciliary Doublet Microtubule

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Ma, Meisheng, Stoyanova, Mihaela, Rademacher, Griffin, Dutcher, Susan K., Brown, Alan, Zhang, Rui·2019·Cell
DOI 10.1016/j.cell.2019.09.030PMC PMC6936269
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Abstract

The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme assembly, structure, and motility require a radially arranged set of doublet microtubules, each decorated in repeating patterns with non-tubulin components. We use single-particle cryo-electron microscopy to visualize and build an atomic model of the repeating structure of a native axonemal doublet microtubule, which reveals the identities, positions, repeat lengths, and interactions of 38 associated proteins, including 33 microtubule inner proteins (MIPs). The structure demonstrates how these proteins establish the unique architecture of doublet microtubules, maintain coherent periodicities along the axoneme, and stabilize the microtubules against the repeated mechanical stress induced by ciliary motility. Our work elucidates the architectural principles that underpin the assembly of this large, repetitive eukaryotic structure and provides a molecular basis for understanding the etiology of human ciliopathies.

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Crossref · 10.1016/j.cell.2019.09.030

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  • The inner junction is well positioned to act as a scaffold for the radial spoke and dynein regulatory complex machinery.

    “Based on near-atomic-resolution cryo-electron microscopy reconstructions of motile cilia axonemes, the inner junction is well positioned to act as a scaffold for the radial spoke and dynein regulatory complex machinery19–22.”

    From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [19]

    In Results (‘MIPs at the outer and inner junctions’; page unavailable), the paper places an opening in the inner-junction FAP20/PACRG ladder near the N-DRC baseplate. But Results (‘The 96-nm external repeat structure’; page unavailable) identifies CCDC39/40, rather than the inner junction, as defining binding sites corresponding to radial-spoke bases and the N-DRC. The proposed scaffold role of the inner junction is therefore not established by this paper. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Proteins at or near the inner junction, including CFAP20, PACRG, CFAP45, CFAP52, CFAP90, CFAP126 and EFHC1, are positioned to form a potential scaffold for, or functionally influence, the radial spokes and dynein regulatory complex that regulates ciliary motility.

    “From cryo-EM structures of Chlamydomonas and Tetrahymena motile cilia, proteins at or near the inner junction, which include CFAP20, PACRG, CFAP45, CFAP52, CFAP90, CFAP126 and EFHC119–21, are all positioned to form a potential scaffold for, or functionally influence, the radial spokes and dynein regulatory complex that regulates ciliary motility (Fig. 8).”

    From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [19]

    The Results section, “MIPs at the outer and inner junctions” (page unavailable), places FAP20 and PACRG at the inner junction, FAP52 adjacent to it, and one PACRG copy near the N-DRC baseplate. The Discussion, “Diverse MIP functions” (page unavailable), describes structural roles for these proteins and FAP45, but our copy does not establish the stated positioning of CFAP90, CFAP126, and EFHC1 or propose that the listed proteins collectively scaffold or influence the radial spokes and N-DRC. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Recent studies position CFAP20 specifically as a core inner junction protein.

    “Recent studies position CFAP20 specifically as a core inner junction protein16,19,20 (Fig. 1b).”

    From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [19]

  • There is a discontinuity in the CFAP20-PACRG arrangement at the inner junction, where a periodic absence of PACRG coincides with the association of the N-DRC with the axoneme.

    “Remarkably, there is even a discontinuity in the CFAP20-PACRG arrangement at the inner junction, where a periodic absence of PACRG coincides with the association of the N-DRC (Nexin-Dynein Regulatory Complex) with the axoneme19,20.”

    From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [19]

  • The multiple contacts of CFAP20 with ciliary axoneme tubulins and PACRG, as well as proximity to CFAP52 and other proteins at or near the inner junction, could explain the degree of conservation of CFAP20.

    “The multiple contacts of CFAP20 with ciliary axoneme tubulins and PACRG, as well as proximity to CFAP52 and other proteins at or near the inner junction19–21,71 (Figs. 1b and 8), could explain this degree of conservation.”

    From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [19]

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Authors
Ma, M., Stoyanova, M., Rademacher, G., Dutcher, S. K., Brown, A., & Zhang, R.
Affiliations
  • Washington University in St. Louis (US)
  • Harvard University (US)
Corresponding author
  • Brown, Alan
  • Zhang, Rui
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-10
Volume
179
Issue
4
Pages
909-922.e12
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.09.030
PMC
PMC6936269
OpenAlex
W2982036345
Cited by
290
References
135
Citations by year
2026: 35 · 2025: 51 · 2024: 43 · 2023: 58 · 2022: 48 · 2021: 30 · 2020: 22 · 2019: 2 · 2018: 1
FWCI
15.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • International Retinal Research Foundation
  • Pew Charitable Trusts
  • E. Matilda Ziegler Foundation for the Blind
  • National Institute of General Medical Sciences
  • Richard and Susan Smith Family Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
axoneme, motile cilia, doublet microtubules, microtubule inner proteins, ciliopathies, axoneme assembly, microtubule stabilization, ciliary motility, atomic structure
MeSH terms
Ciliopathies, Cell Movement, Cilia, Humans, Microtubule Proteins, Microtubules, Stress, Mechanical, Cryoelectron Microscopy, Axoneme

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