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5ajk

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Revision as of 09:55, 10 March 2017

Crystal structure of variola virus virulence factor F1L in complex with human Bak BH3 domain

Structural highlights

5ajk is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5ajj
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[BAK_HUMAN] In the presence of an appropriate stimulus, accelerates programmed cell death by binding to, and antagonizing the anti-apoptotic action of BCL2 or its adenovirus homolog E1B 19k protein. Low micromolar levels of zinc ions inhibit the promotion of apoptosis.^[1] ^[2]

Publication Abstract from PubMed

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism.

Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim.,Marshall B, Puthalakath H, Caria S, Chugh S, Doerflinger M, Colman PM, Kvansakul M Cell Death Dis. 2015 Mar 12;6:e1680. doi: 10.1038/cddis.2015.52. PMID:25766319^[3]

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

References

↑ Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 1995 Nov 15;14(22):5589-96. PMID:8521816
↑ Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell. 2006 Dec 8;24(5):677-88. PMID:17157251 doi:10.1016/j.molcel.2006.10.014
↑ Marshall B, Puthalakath H, Caria S, Chugh S, Doerflinger M, Colman PM, Kvansakul M. Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim. Cell Death Dis. 2015 Mar 12;6:e1680. doi: 10.1038/cddis.2015.52. PMID:25766319 doi:http://dx.doi.org/10.1038/cddis.2015.52

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/5ajk"

@@ Line 1: / Line 1: @@
 ==Crystal structure of variola virus virulence factor F1L in complex with human Bak BH3 domain==
 <StructureSection load='5ajk' size='340' side='right' caption='[[5ajk]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ajj|5ajj]]</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=5ajk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ajk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5ajk RCSB], [http://www.ebi.ac.uk/pdbsum/5ajk PDBsum]</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=5ajk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ajk OCA], [http://pdbe.org/5ajk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ajk RCSB], [http://www.ebi.ac.uk/pdbsum/5ajk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ajk ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 5ajk" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5ajk

From Proteopedia

Revision as of 09:55, 10 March 2017

Crystal structure of variola virus virulence factor F1L in complex with human Bak BH3 domain

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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