Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.81977
Keywords
motile cilia; integrative structural biology; cross-linking mass spectrometry; intraflagellar transport; Tetrahymena thermophila; Chlamydomonas reinhardtii; Homo sapiens
Categories
Funding
- 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]
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Intraflagellar transport (IFT) is a crucial process for cargo transport in cilia and is associated with the etiology of genetic diseases. This study combines experimental and computational approaches to determine the overall structure of IFT and provide insights into the pleiotropic nature of ciliopathy-associated genetic variants.
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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