ArticleNature structural & molecular biology2016
Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function.
Article in Nature structural & molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 63 citations in OpenAlex.
- Article
- Functional characterization of a human epilepsy-associated gene network reveals metabolic regulation as a critical factor underlying seizure susceptibilities.Disease models & mechanisms · 2026Article
- Discovery and Characterization of a Selective Inhibitor of Synaptojanin1 5‑Phosphatase Activity.ACS pharmacology & translational science · 2025Article
- Article
- Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism.Cell reports. Medicine · 2024Article
- Interaction between the TBC1D24 TLDc domain and the KIBRA C2 domain is disrupted by two epilepsy-associated TBC1D24 missense variants.The Journal of biological chemistry · 2024Article
- Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss.Scientific reports · 2024Article
- Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1.NPJ Parkinson's disease · 2023Article
- Addition of an affected family member to a previously ascertained autosomal recessive nonsyndromic hearing loss pedigree and systematic phenotype-genotype analysis of splice-site variants in MYO15A.BMC medical genomics · 2022Article
- The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction.Molecular neurobiology · 2022Article
- Crystal structure of the TLDc domain of human NCOA7-AS.Acta crystallographica. Section F, Structural biology communications · 2021Article
- TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss.Scientific reports · 2021Article
- The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour.Cellular and molecular life sciences : CMLS · 2021Article
- DOORS syndrome and a recurrent truncating ATP6V1B2 variant.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Personalized Medicine Using Cutting Edge Technologies for Genetic Epilepsies.Current neuropharmacology · 2021Review
- Article
- Dictyostelium discoideum as a non-mammalian biomedical model.Microbial biotechnology · 2021Review
- Investigating rare and ultrarare epilepsy syndromes withFaculty reviews · 2021Review
- Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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)P
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.