Projecten per jaar
Samenvatting
Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. Cocrystallization and biochemistry showed that this pocket binds phosphoinositides phosphorylated at the 4 and 5 positions. The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding. Using in vivo photobleaching of Skywalker-GFP mutants, including pathogenic mutants, we showed that membrane binding via this pocket restricts Skywalker diffusion in presynaptic terminals. Additionally, the pathogenic mutations cause severe neurological defects in flies, including impaired synaptic-vesicle trafficking and seizures, and these defects are reversed by genetically increasing synaptic PI(4,5)P2 concentrations through synaptojanin mutations. Hence, we discovered that a TBC domain affected by clinical mutations directly binds phosphoinositides through a cationic pocket and that phosphoinositide binding is critical for presynaptic function.
Originele taal-2 | English |
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Pagina's (van-tot) | 965-973 |
Aantal pagina's | 9 |
Tijdschrift | Nature Structural and Molecular Biology |
Volume | 23 |
Nummer van het tijdschrift | 11 |
DOI's | |
Status | Published - nov 2016 |
Vingerafdruk
Duik in de onderzoeksthema's van 'Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function'. Samen vormen ze een unieke vingerafdruk.Projecten
- 1 Afgelopen
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SRP34: SRP (Groeiers): Het verre bereik van enzymologie in gezondheid en ziekte - Kinetiek langs signaaltransductiewegen in complexe systemen
1/03/14 → 28/02/19
Project: Fundamenteel
Onderzoekersoutput
- 51 Citaties
- 2 Poster
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Revealing the function of TBC1D24 mutations in epilepsy and related neurological diseases
Paesmans, J., Versees, W., Fischer, B., Verstreken, P. & Lüthy, K., 8 feb 2018, (Unpublished).Onderzoeksoutput: Poster
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TBC1D24-skywalker has a lipid-binding pocket mutated in epilepsy and required for synaptic function
Paesmans, J., Versees, W., Fischer, B., Verstreken, P. & Lüthy, K., 9 mei 2018, (Unpublished).Onderzoeksoutput: Poster
Activiteiten
- 1 Talk or presentation at a workshop/seminar
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EMBO Molecular Neurobiology workshop
Jone Paesmans (Speaker), Wim Versees (Contributor), Baptiste Fischer (Contributor), Patrik Verstreken (Contributor) & Kevin Lüthy (Contributor)
8 mei 2018 → 12 mei 2018Activiteit: Talk or presentation at a workshop/seminar