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Molecular Basis of Tubulin Transport During Cilium Formation

Project description

Dissecting cilia formation on cells

Cilia are cylindrical organelles present in eukaryotic cells consisting of microtubules in a defined organisational pattern maintained by the intraflagellar transport (IFT) complex. Scientists of the EU-funded ciTTub project are working on dissecting the mechanism by which IFT delivers building blocks and contributes to cilium homeostasis. Using a combination of biochemistry, X-ray crystallography and single-particle cryo-electron microscopy techniques, ciTTub will unveil cilium biogenesis at atomic resolution with important implications for the treatment of ciliopathies.

Objective

Cilia are essential hair-like structures presented at the surface of eukaryotic cells that allow motility, fluid flow and complex inter- and intracellular signalling events. Nine pairs of microtubules organized in a cylindrical shape called axoneme form the backbone of cilia. The formation and maintenance of cilia is dependent on a multi-subunit protein complex termed the intraflagellar transport (IFT) complex that actively delivers axonemal building blocks such as tubulin from the base to the tip of growing cilia. Lack of cilia or its miss-construction leads to severe developmental diseases called ciliopathies. Despite its fundamental role in cilium biogenesis, the process of tubulin recruitment, loading and unloading by the IFT machinery remains poorly understood. In this proposal, I aim to elucidate the mechanism of tubulin loading onto IFT complexes by determining high-resolution structures of intraflagellar transport (IFT) complexes bound to tubulin. Details about the IFT-tubulin interaction interface will be obtained by a combination of biochemical techniques like site directed photo- and chemical crosslinking followed by mass-spectrometry analysis and the structural biology techniques X-ray crystallography and single particle cryo-electron microscopy (cryo-EM). Ultimately, this study will enrich our understanding of cilium biogenesis and homeostasis by providing the first insight at atomic resolution into cargo selection and loading onto IFT machinery.

Coordinator

AARHUS UNIVERSITET
Net EU contribution
€ 219 312,00
Address
NORDRE RINGGADE 1
8000 Aarhus C
Denmark

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Region
Danmark Midtjylland Østjylland
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 219 312,00