|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of human ceramide-1-phosphate transfer protein (CPTP) in complex with 16:0 ceramide-1-phosphate (16:0-C1P)== | | ==Crystal structure of human ceramide-1-phosphate transfer protein (CPTP) in complex with 16:0 ceramide-1-phosphate (16:0-C1P)== |
| - | <StructureSection load='4k84' size='340' side='right' caption='[[4k84]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4k84' size='340' side='right'caption='[[4k84]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4k84]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K84 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K84 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4k84]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K84 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K84 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PX:(2S,3R,4E)-2-(HEXADECANOYLAMINO)-3-HYDROXYOCTADEC-4-EN-1-YL+DIHYDROGEN+PHOSPHATE'>1PX</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]] 1.897Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4k80|4k80]], [[4k85|4k85]], [[4k8n|4k8n]], [[4kf6|4kf6]], [[4kbs|4kbs]], [[4kbr|4kbr]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PX:(2S,3R,4E)-2-(HEXADECANOYLAMINO)-3-HYDROXYOCTADEC-4-EN-1-YL+DIHYDROGEN+PHOSPHATE'>1PX</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLTPD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4k84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k84 OCA], [https://pdbe.org/4k84 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k84 RCSB], [https://www.ebi.ac.uk/pdbsum/4k84 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k84 ProSAT]</span></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=4k84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k84 OCA], [http://pdbe.org/4k84 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k84 RCSB], [http://www.ebi.ac.uk/pdbsum/4k84 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k84 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/CPTP_HUMAN CPTP_HUMAN] Mediates the intracellular transfer of ceramide-1-phosphate (C1P) between organelle membranes and the cell membrane. Required for normal structure of the Golgi stacks. Can bind phosphoceramides with a variety of aliphatic chains, but has a preference for lipids with saturated C16:0 or monounsaturated C18:1 aliphatic chains, and is inefficient with phosphoceramides containing lignoceryl (C24:0). Plays a role in the regulation of the cellular levels of ceramide-1-phosphate, and thereby contributes to the regulation of phospholipase PLA2G4A activity and the release of arachidonic acid. Has no activity with galactosylceramide, lactosylceramide, sphingomyelin, phosphatidylcholine, phosphatidic acid and ceramide. C1P transfer is stimulated by phosphatidylserine in C1P source vesicles (PubMed:28011644). Regulates autophagy, inflammasome mediated IL1B and IL18 processing, and pyroptosis, but not apoptosis (PubMed:29164996).<ref>PMID:23863933</ref> <ref>PMID:28011644</ref> <ref>PMID:29164996</ref> |
| - | Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2alpha (cPLA2alpha), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, alpha-helically-dominated 'sandwich' topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2alpha release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.
| + | |
| - | | + | |
| - | Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids.,Simanshu DK, Kamlekar RK, Wijesinghe DS, Zou X, Zhai X, Mishra SK, Molotkovsky JG, Malinina L, Hinchcliffe EH, Chalfant CE, Brown RE, Patel DJ Nature. 2013 Aug 22;500(7463):463-7. doi: 10.1038/nature12332. Epub 2013 Jul 17. PMID:23863933<ref>PMID:23863933</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div> | + | |
| - | <div class="pdbe-citations 4k84" style="background-color:#fffaf0;"></div> | + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Brown, R E]] | + | [[Category: Large Structures]] |
| - | [[Category: Patel, D J]] | + | [[Category: Brown RE]] |
| - | [[Category: Simanshu, D K]] | + | [[Category: Patel DJ]] |
| - | [[Category: C1p]] | + | [[Category: Simanshu DK]] |
| - | [[Category: Ceramide-1-phosphate]]
| + | |
| - | [[Category: Cptp]]
| + | |
| - | [[Category: Eicosanoid]]
| + | |
| - | [[Category: Gltp-fold]]
| + | |
| - | [[Category: Lipid transfer protein]]
| + | |
| - | [[Category: Lipid transport]]
| + | |
| - | [[Category: Protein-lipid complex]]
| + | |
| Structural highlights
Function
CPTP_HUMAN Mediates the intracellular transfer of ceramide-1-phosphate (C1P) between organelle membranes and the cell membrane. Required for normal structure of the Golgi stacks. Can bind phosphoceramides with a variety of aliphatic chains, but has a preference for lipids with saturated C16:0 or monounsaturated C18:1 aliphatic chains, and is inefficient with phosphoceramides containing lignoceryl (C24:0). Plays a role in the regulation of the cellular levels of ceramide-1-phosphate, and thereby contributes to the regulation of phospholipase PLA2G4A activity and the release of arachidonic acid. Has no activity with galactosylceramide, lactosylceramide, sphingomyelin, phosphatidylcholine, phosphatidic acid and ceramide. C1P transfer is stimulated by phosphatidylserine in C1P source vesicles (PubMed:28011644). Regulates autophagy, inflammasome mediated IL1B and IL18 processing, and pyroptosis, but not apoptosis (PubMed:29164996).[1] [2] [3]
References
- ↑ Simanshu DK, Kamlekar RK, Wijesinghe DS, Zou X, Zhai X, Mishra SK, Molotkovsky JG, Malinina L, Hinchcliffe EH, Chalfant CE, Brown RE, Patel DJ. Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature. 2013 Aug 22;500(7463):463-7. doi: 10.1038/nature12332. Epub 2013 Jul 17. PMID:23863933 doi:10.1038/nature12332
- ↑ Zhai X, Gao YG, Mishra SK, Simanshu DK, Boldyrev IA, Benson LM, Bergen HR 3rd, Malinina L, Mundy J, Molotkovsky JG, Patel DJ, Brown RE. Phosphatidylserine Stimulates Ceramide 1-Phosphate (C1P) Intermembrane Transfer by C1P Transfer Proteins. J Biol Chem. 2017 Feb 10;292(6):2531-2541. doi: 10.1074/jbc.M116.760256. Epub , 2016 Dec 23. PMID:28011644 doi:http://dx.doi.org/10.1074/jbc.M116.760256
- ↑ Mishra SK, Gao YG, Deng Y, Chalfant CE, Hinchcliffe EH, Brown RE. CPTP: A sphingolipid transfer protein that regulates autophagy and inflammasome activation. Autophagy. 2018;14(5):862-879. doi: 10.1080/15548627.2017.1393129. Epub 2018 Feb , 21. PMID:29164996 doi:http://dx.doi.org/10.1080/15548627.2017.1393129
|
