FAP106 is an interaction hub for assembling microtubule inner proteins at the cilium inner junction
Open accessPublished version of a preprint
Abstract
Motility of pathogenic protozoa depends on flagella (synonymous with cilia) with axonemes containing nine doublet microtubules (DMTs) and two singlet microtubules. Microtubule inner proteins (MIPs) within DMTs influence axoneme stability and motility and provide lineage-specific adaptations, but individual MIP functions and assembly mechanisms are mostly unknown. Here, we show in the sleeping sickness parasite Trypanosoma brucei , that FAP106, a conserved MIP at the DMT inner junction, is required for trypanosome motility and functions as a critical interaction hub, directing assembly of several conserved and lineage-specific MIPs. We use comparative cryogenic electron tomography (cryoET) and quantitative proteomics to identify MIP candidates. Using RNAi knockdown together with fitting of AlphaFold models into cryoET maps, we demonstrate that one of these candidates, MC8, is a trypanosome-specific MIP required for parasite motility. Our work advances understanding of MIP assembly mechanisms and identifies lineage-specific motility proteins that are attractive targets to consider for therapeutic intervention.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Fast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2022) · doi:10.1101/2022.02.07.479398 · Cited by 2,598 · see citing works
Fast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-01773-0 · Cited by 2,596 · see citing works
Khalifa, A. A. Z., Ichikawa, M., Dai, D., Kubo, S., Black, C. S., Peri, K., McAlear, T. S., Veyron, S., Yang, S. K., Vargas, J., et al. (2020) · eLife · doi:10.7554/elife.52760 · Cited by 1,676 · see citing works
Inner lumen proteins stabilize doublet microtubules in cilia and flagella
Owa, M., Uchihashi, T., Yanagisawa, H.-A., Yamano, T., Iguchi, H., Fukuzawa, H., Wakabayashi, K.-I., Ando, T., & Kikkawa, M. (2019) · Nature Communications · doi:10.1038/s41467-019-09051-x · Cited by 140 · see citing works
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“Some organisms have multiple PACRG homologs 17,41,52 .”
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- Authors
- Shimogawa, M. M., Wijono, A. S., Wang, H., Zhang, J., Sha, J., Szombathy, N., Vadakkan, S., Pelayo, P., Jonnalagadda, K., Wohlschlegel, J., Zhou, Z. H., & Hill, K. L.
- Affiliations
- University of California, Los Angeles (US)
- California NanoSystems Institute (US)
- Corresponding author
- Zhou, Z. Hong
- Hill, Kent L.
- ORCID
- Venue
- Nature Communications
- Published
- 2023-08-26
- Volume
- 14
- Issue
- 1
- Pages
- 5225-5225
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10460401
- OpenAlex
- W4386195805
- Cited by
- 18
- References
- 6
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI052348)
- Arnold and Mabel Beckman Foundation (Beckman Scholars Program)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM089778, GM071940)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- microtubule inner proteins, axoneme, flagella, cilia, doublet microtubules, Trypanosoma brucei, sleeping sickness, parasite motility, protein assembly, AlphaFold models
- MeSH terms
- Acclimatization, Cilia, Flagella, Microtubule Proteins, Microtubules, Axoneme
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