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1h0j

From Proteopedia

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Current revision

Structural Basis of the Membrane-induced Cardiotoxin A3 Oligomerization

Structural highlights

1h0j is a 3 chain structure with sequence from Naja atra. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 (CTXs) have previously been shown to induce membrane fusion of vesicles formed by phospholipids such as cardiolipin or sphingomyelin. CTX can also form a pore in membrane bilayers containing a anionic lipid such as phosphatidylserine or phosphatidylglycerol. Herein, we show that the interaction of CTX with negatively charged lipids causes CTX dimerization, an important intermediate for the eventual oligomerization of CTX during the CTX-induced fusion and pore formation process. The structural basis of the lipid-induced oligomerization of CTX A3, a major CTX from Naja atra, is then illustrated by the crystal structure of CTX A3 in complex with SDS; SDS likely mimics anionic lipids of the membrane under micelle conditions at 1.9-A resolution. The crystal packing reveals distinct SDS-free and SDS-rich regions; in the latter two types of interconnecting CTX A3 dimers, D1 and D2, and several SDS molecules can be identified to stabilize D1 and D2 by simultaneously interacting with residues at each dimer interface. When the three CTXSDS complexes in the asymmetric unit are overlaid, the orientation of CTX A3 monomers relative to the SDS molecules in the crystal is strikingly similar to that of the toxin with respect to model membranes as determined by NMR and Fourier transform infrared methods. These results not only illustrate how lipid-induced CTX dimer formation may be transformed into oligomers either as inverted micelles of fusion intermediates or as membrane pore of anionic lipid bilayers but also underscore a potential role for SDS in x-ray diffraction study of protein-membrane interactions in the future.

Structural basis of membrane-induced cardiotoxin A3 oligomerization.,Forouhar F, Huang WN, Liu JH, Chien KY, Wu WG, Hsiao CD J Biol Chem. 2003 Jun 13;278(24):21980-8. Epub 2003 Mar 26. PMID:12660250^[8]

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

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
↑ Forouhar F, Huang WN, Liu JH, Chien KY, Wu WG, Hsiao CD. Structural basis of membrane-induced cardiotoxin A3 oligomerization. J Biol Chem. 2003 Jun 13;278(24):21980-8. Epub 2003 Mar 26. PMID:12660250 doi:10.1074/jbc.M208650200

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1h0j"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1h0j]] is a 3 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=1H0J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H0J FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SDS:DODECYL+SULFATE'>SDS</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]] 1.9&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2crs|2crs]], [[2crt|2crt]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SDS:DODECYL+SULFATE'>SDS</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=1h0j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h0j OCA], [https://pdbe.org/1h0j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h0j RCSB], [https://www.ebi.ac.uk/pdbsum/1h0j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h0j ProSAT]</span></td></tr>
 </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 ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 38: @@
 [[Category: Large Structures]]
 [[Category: Naja atra]]
-[[Category: Chien, K Y]]
+[[Category: Chien K-Y]]
-[[Category: Forouhar, F]]
+[[Category: Forouhar F]]
-[[Category: Hsiao, C D]]
+[[Category: Hsiao C-D]]
-[[Category: Huang, W N]]
+[[Category: Huang W-N]]
-[[Category: Liu, J H]]
+[[Category: Liu J-H]]
-[[Category: Wu, W G]]
+[[Category: Wu W-G]]
-[[Category: Cardiotoxin]]
-[[Category: Cytotoxin]]
-[[Category: Sodium dodecyl sulfate]]
-[[Category: Venom]]

1h0j

From Proteopedia

Current revision

Structural Basis of the Membrane-induced Cardiotoxin A3 Oligomerization

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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