Integrative modeling reveals the molecular architecture of the intraflagellar transport A (IFT-A) complex
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Abstract
Intraflagellar transport (IFT) is a conserved process of cargo transport in cilia that is essential for development and homeostasis in organisms ranging from algae to vertebrates. In humans, variants in genes encoding subunits of the cargo-adapting IFT-A and IFT-B protein complexes are a common cause of genetic diseases known as ciliopathies. While recent progress has been made in determining the atomic structure of IFT-B, little is known of the structural biology of IFT-A. Here, we combined chemical cross-linking mass spectrometry and cryo-electron tomography with AlphaFold2-based prediction of both protein structures and interaction interfaces to model the overall architecture of the monomeric six-subunit IFT-A complex, as well as its polymeric assembly within cilia. We define monomer-monomer contacts and membrane-associated regions available for association with transported cargo, and we also use this model to provide insights into the pleiotropic nature of human ciliopathy-associated genetic variants in genes encoding IFT-A subunits. Our work demonstrates the power of integration of experimental and computational strategies both for multi-protein structure determination and for understanding the etiology of human genetic disease.
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Cites
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McCafferty, C. L., Pennington, E. L., Papoulas, O., Taylor, D. W., & Marcotte, E. M. (2023) · Communications Biology · doi:10.1038/s42003-023-04773-7 · Cited by 35 · see citing works
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- Authors
- McCafferty, C. L., Papoulas, O., Jordan, M. A., Hoogerbrugge, G., Nichols, C., Pigino, G., Taylor, D. W., Wallingford, J. B., & Marcotte, E. M.
- Affiliations
- Department of Molecular Biosciences, Center for Systems and Synthetic Biology, University of Texas
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Human Technopole (IT)
- Corresponding author
- McCafferty, Caitlyn L
- Marcotte, Edward M
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-11-08
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9674347
- OpenAlex
- W4308555726
- Cited by
- 40
- References
- 11
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 5 · 2023: 14 · 2022: 7
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (2019238253)
- National Institute of General Medical Sciences (R35GM122480, R35GM138348)
- National Institute of Child Health and Human Development (HD085901)
- Army Research Office (W911NF-12-1-0390)
- Welch Foundation (F-1515, F-1938)
- Max Planck Society
- Cancer Prevention and Research Institute of Texas (RR160088)
- Human Technopole
- 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 › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- IFT-A complex, cilia, ciliopathies, protein complex structure, freight transport, integrative structural modeling, AlphaFold2
- MeSH terms
- Ciliopathies, Animals, Biological Transport, Cilia, Homeostasis, Humans, Electron Microscope Tomography
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