5hjn
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the TBC domain of Skywalker/TBC1D24 from Drosophila melanogaster== | |
| + | <StructureSection load='5hjn' size='340' side='right'caption='[[5hjn]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5hjn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HJN FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.501Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5hjn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hjn OCA], [https://pdbe.org/5hjn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hjn RCSB], [https://www.ebi.ac.uk/pdbsum/5hjn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hjn ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/SKY_DROME SKY_DROME] GTPase-activating protein (GAP) for Rab35 which regulates synaptic vesicle (SV) protein recycling and turnover at the neuromuscular junction boutons and possibly ventral nerve cord via endosomal trafficking (PubMed:21458671, PubMed:25422373, PubMed:27669036). Inhibits Rab35-mediated endosomal sorting which traffics old or dysfunctional SV proteins through a degradative endolysosomal route that involves the ESCRT pathway and the HOPS complex members dor, vps39 and rab7 (PubMed:21458671, PubMed:25422373). This function is essential for preventing excessive degradation and turnover of vesicles from the readily releasable pool which leads to increased neurotransmission and eventually neurodegeneration (PubMed:21458671, PubMed:25422373, PubMed:27669036). Preferentially binds phosphoinositides phosphorylated at the D5 position of the inositol ring, such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:27669036). Binding to phosphoinositides and thus membrane-association, is required for its function in regulating the turnover of synaptic-vesicle proteins (PubMed:27669036). It is therefore likely that it is recruited to vesicle membranes with high phosphoinositide content and thereby selectively prevents endolysosomal degradation of these vesicles (PubMed:27669036).<ref>PMID:21458671</ref> <ref>PMID:25422373</ref> <ref>PMID:27669036</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| - | + | Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function.,Fischer B, Luthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versees W Nat Struct Mol Biol. 2016 Sep 26. doi: 10.1038/nsmb.3297. PMID:27669036<ref>PMID:27669036</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5hjn" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Drosophila melanogaster]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Fischer B]] | ||
| + | [[Category: Paesmans J]] | ||
| + | [[Category: Versees W]] | ||
Current revision
Crystal structure of the TBC domain of Skywalker/TBC1D24 from Drosophila melanogaster
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