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| | ==Crystal structure of Taiwan cobra cardiotoxin A3 complexed with sulfogalactoceramide== | | ==Crystal structure of Taiwan cobra cardiotoxin A3 complexed with sulfogalactoceramide== |
| - | <StructureSection load='2bhi' size='340' side='right' caption='[[2bhi]], [[Resolution|resolution]] 2.31Å' scene=''> | + | <StructureSection load='2bhi' size='340' side='right'caption='[[2bhi]], [[Resolution|resolution]] 2.31Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2bhi]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Naja_atra Naja atra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2BHI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2bhi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Naja_atra Naja atra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BHI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C10:HEXAETHYLENE+GLYCOL+MONODECYL+ETHER'>C10</scene>, <scene name='pdbligand=SFT:SULFOGALACTOCERAMIDE'>SFT</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]] 2.31Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1h0j|1h0j]], [[1i02|1i02]], [[1xt3|1xt3]], [[2crs|2crs]], [[2crt|2crt]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C10:HEXAETHYLENE+GLYCOL+MONODECYL+ETHER'>C10</scene>, <scene name='pdbligand=SFT:SULFOGALACTOCERAMIDE'>SFT</scene></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=2bhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bhi OCA], [http://pdbe.org/2bhi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2bhi RCSB], [http://www.ebi.ac.uk/pdbsum/2bhi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2bhi ProSAT]</span></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=2bhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bhi OCA], [https://pdbe.org/2bhi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bhi RCSB], [https://www.ebi.ac.uk/pdbsum/2bhi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bhi ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/3SA3_NAJAT 3SA3_NAJAT] Basic protein that binds to cell membrane and depolarizes cardiomyocytes. This cytotoxin also possesses lytic activity on many other cells, including red blood cells (PubMed:8182052). Interaction with sulfatides in the cell membrane induces pore formation and cell internalization. Cytotoxicity is due to pore formation, and to another mechanism independent of membrane-damaging activity. When internalized, it targets the mitochondrial membrane and induces mitochondrial swelling and fragmentation. It inhibits protein kinases C. It binds to the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity (PubMed:16407244). It also binds with high affinity to heparin (PubMed:17685633).<ref>PMID:15922335</ref> <ref>PMID:16263708</ref> <ref>PMID:16407244</ref> <ref>PMID:17714752</ref> <ref>PMID:8182052</ref> <ref>PMID:8448165</ref> <ref>PMID:9245415</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Cardiotoxin|Cardiotoxin]] | + | *[[Cardiotoxin 3D structures|Cardiotoxin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Naja atra]] | | [[Category: Naja atra]] |
| - | [[Category: Hsiao, C D]] | + | [[Category: Hsiao C-D]] |
| - | [[Category: Lee, S C]] | + | [[Category: Lee S-C]] |
| - | [[Category: Liu, J H]] | + | [[Category: Liu J-H]] |
| - | [[Category: Wang, C H]] | + | [[Category: Wang C-H]] |
| - | [[Category: Wu, P L]] | + | [[Category: Wu P-L]] |
| - | [[Category: Wu, W G]] | + | [[Category: Wu W-G]] |
| - | [[Category: Cardiotoxin]]
| + | |
| - | [[Category: Cobra cardiotoxin]]
| + | |
| - | [[Category: Cytolysis]]
| + | |
| - | [[Category: Glycosphingolipid]]
| + | |
| - | [[Category: Membrane pore formation]]
| + | |
| - | [[Category: Sulfogalactoceramide sulfatide]]
| + | |
| Structural highlights
Function
3SA3_NAJAT Basic protein that binds to cell membrane and depolarizes cardiomyocytes. This cytotoxin also possesses lytic activity on many other cells, including red blood cells (PubMed:8182052). Interaction with sulfatides in the cell membrane induces pore formation and cell internalization. Cytotoxicity is due to pore formation, and to another mechanism independent of membrane-damaging activity. When internalized, it targets the mitochondrial membrane and induces mitochondrial swelling and fragmentation. It inhibits protein kinases C. It binds to the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity (PubMed:16407244). It also binds with high affinity to heparin (PubMed:17685633).[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Cobra cardiotoxins, a family of basic polypeptides having lipid- and heparin-binding capacities similar to the cell-penetrating peptides, induce severe tissue necrosis and systolic heart arrest in snakebite victims. Whereas cardiotoxins are specifically retained on the cell surface via heparan sulfate-mediated processes, their lipid binding ability appears to be responsible, at least in part, for cardiotoxin-induced membrane leakage and cell death. Although the exact role of lipids involved in toxin-mediated cytotoxicity remains largely unknown, monoclonal anti-sulfatide antibody O4 has recently been shown to inhibit the action of CTX A3, the major cardiotoxin from Taiwan cobra venom, on cardiomyocytes by preventing cardiotoxin-induced membrane leakage and CTX A3 internalization into mitochondria. Here, we show that anti-sulfatide acts by blocking the binding of CTX A3 to the sulfatides in the plasma membrane to prevent sulfatide-dependent CTX A3 membrane pore formation and internalization. We also describe the crystal structure of a CTX A3-sulfatide complex in a membrane-like environment at 2.3 angstroms resolution. The unexpected orientation of the sulfatide fatty chains in the structure allows prediction of the mode of toxin insertion into the plasma membrane. CTX A3 recognizes both the headgroup and the ceramide interfacial region of sulfatide to induce a lipid conformational change that may play a key role in CTX A3 oligomerization and cellular internalization. This proposed lipid-mediated toxin translocation mechanism may also shed light on the cellular uptake mechanism of the amphiphilic cell-penetrating peptides known to involve multiple internalization pathways.
Glycosphingolipid-facilitated membrane insertion and internalization of cobra cardiotoxin. The sulfatide.cardiotoxin complex structure in a membrane-like environment suggests a lipid-dependent cell-penetrating mechanism for membrane binding polypeptides.,Wang CH, Liu JH, Lee SC, Hsiao CD, Wu WG J Biol Chem. 2006 Jan 6;281(1):656-67. Epub 2005 Nov 1. PMID:16263708[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang CH, Wu WG. Amphiphilic beta-sheet cobra cardiotoxin targets mitochondria and disrupts its network. FEBS Lett. 2005 Jun 6;579(14):3169-74. PMID:15922335 doi:http://dx.doi.org/S0014-5793(05)00579-X
- ↑ Wang CH, Liu JH, Lee SC, Hsiao CD, Wu WG. Glycosphingolipid-facilitated membrane insertion and internalization of cobra cardiotoxin. The sulfatide.cardiotoxin complex structure in a membrane-like environment suggests a lipid-dependent cell-penetrating mechanism for membrane binding polypeptides. J Biol Chem. 2006 Jan 6;281(1):656-67. Epub 2005 Nov 1. PMID:16263708 doi:10.1074/jbc.M507880200
- ↑ Wu PL, Lee SC, Chuang CC, Mori S, Akakura N, Wu WG, Takada Y. Non-cytotoxic cobra cardiotoxin A5 binds to alpha(v)beta3 integrin and inhibits bone resorption. Identification of cardiotoxins as non-RGD integrin-binding proteins of the Ly-6 family. J Biol Chem. 2006 Mar 24;281(12):7937-45. Epub 2006 Jan 10. PMID:16407244 doi:http://dx.doi.org/M513035200
- ↑ Chen KC, Kao PH, Lin SR, Chang LS. The mechanism of cytotoxicity by Naja naja atra cardiotoxin 3 is physically distant from its membrane-damaging effect. Toxicon. 2007 Nov;50(6):816-24. Epub 2007 Jun 27. PMID:17714752 doi:http://dx.doi.org/S0041-0101(07)00224-3
- ↑ Chien KY, Chiang CM, Hseu YC, Vyas AA, Rule GS, Wu W. Two distinct types of cardiotoxin as revealed by the structure and activity relationship of their interaction with zwitterionic phospholipid dispersions. J Biol Chem. 1994 May 20;269(20):14473-83. PMID:8182052
- ↑ Chiou SH, Raynor RL, Zheng B, Chambers TC, Kuo JF. Cobra venom cardiotoxin (cytotoxin) isoforms and neurotoxin: comparative potency of protein kinase C inhibition and cancer cell cytotoxicity and modes of enzyme inhibition. Biochemistry. 1993 Mar 2;32(8):2062-7. PMID:8448165
- ↑ Sue SC, Rajan PK, Chen TS, Hsieh CH, Wu W. Action of Taiwan cobra cardiotoxin on membranes: binding modes of a beta-sheet polypeptide with phosphatidylcholine bilayers. Biochemistry. 1997 Aug 12;36(32):9826-36. PMID:9245415 doi:http://dx.doi.org/10.1021/bi970413l
- ↑ Wang CH, Liu JH, Lee SC, Hsiao CD, Wu WG. Glycosphingolipid-facilitated membrane insertion and internalization of cobra cardiotoxin. The sulfatide.cardiotoxin complex structure in a membrane-like environment suggests a lipid-dependent cell-penetrating mechanism for membrane binding polypeptides. J Biol Chem. 2006 Jan 6;281(1):656-67. Epub 2005 Nov 1. PMID:16263708 doi:10.1074/jbc.M507880200
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