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5hjq

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Crystal structure of the TBC domain of Skywalker/TBC1D24 from Drosophila melanogaster in complex with inositol(1,4,5)triphosphate

Structural highlights

5hjq is a 1 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Uytterhoeven V, Kuenen S, Kasprowicz J, Miskiewicz K, Verstreken P. Loss of skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell. 2011 Apr 1;145(1):117-32. doi: 10.1016/j.cell.2011.02.039. PMID:21458671 doi:http://dx.doi.org/10.1016/j.cell.2011.02.039
↑ Fernandes AC, Uytterhoeven V, Kuenen S, Wang YC, Slabbaert JR, Swerts J, Kasprowicz J, Aerts S, Verstreken P. Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol. 2014 Nov 24;207(4):453-62. doi: 10.1083/jcb.201406026. PMID:25422373 doi:http://dx.doi.org/10.1083/jcb.201406026
↑ Fischer B, Luthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versees W. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016 Sep 26. doi: 10.1038/nsmb.3297. PMID:27669036 doi:http://dx.doi.org/10.1038/nsmb.3297
↑ Fischer B, Luthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versees W. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016 Sep 26. doi: 10.1038/nsmb.3297. PMID:27669036 doi:http://dx.doi.org/10.1038/nsmb.3297

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5hjq"

Categories: Drosophila melanogaster | Large Structures | Fischer B | Paesmans J | Versees W

@@ Line 1: / Line 1: @@
 ==Crystal structure of the TBC domain of Skywalker/TBC1D24 from Drosophila melanogaster in complex with inositol(1,4,5)triphosphate==
-<StructureSection load='5hjq' size='340' side='right' caption='[[5hjq]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='5hjq' size='340' side='right'caption='[[5hjq]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5hjq]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HJQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HJQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5hjq]] 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=5HJQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HJQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=I3P:D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE'>I3P</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5hjq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hjq OCA], [http://pdbe.org/5hjq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hjq RCSB], [http://www.ebi.ac.uk/pdbsum/5hjq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hjq ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I3P:D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE'>I3P</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=5hjq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hjq OCA], [https://pdbe.org/5hjq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hjq RCSB], [https://www.ebi.ac.uk/pdbsum/5hjq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hjq 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 ==
@@ Line 20: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Fischer, B]]
+[[Category: Drosophila melanogaster]]
-[[Category: Paesmans, J]]
+[[Category: Large Structures]]
-[[Category: Versees, W]]
+[[Category: Fischer B]]
-[[Category: Rabgap]]
+[[Category: Paesmans J]]
-[[Category: Signaling protein]]
+[[Category: Versees W]]
-[[Category: Tbc]]

5hjq

From Proteopedia

Current revision

Crystal structure of the TBC domain of Skywalker/TBC1D24 from Drosophila melanogaster in complex with inositol(1,4,5)triphosphate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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