2lr1

From Proteopedia

(Difference between revisions)

Revision as of 11:13, 15 February 2023

Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA

Structural highlights

2lr1 is a 2 chain structure with sequence from Homo sapiens and Human herpesvirus 5 strain AD169. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BAX_HUMAN Accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor BCL2 or its adenovirus homolog E1B 19k protein. Under stress conditions, undergoes a conformation change that causes translocation to the mitochondrion membrane, leading to the release of cytochrome c that then triggers apoptosis. Promotes activation of CASP3, and thereby apoptosis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. Bax exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when Bax is activated by proapoptotic proteins. Activated Bax changes conformation, inserts into the mitochondrial outer membrane (MOM), oligomerizes, and induces MOM permeabilization, causing the release of cytochrome c, which effectively commits the cell to die. Because apoptosis is also a basic defense mechanism against invading pathogens, many viruses have developed counteractive measures. Such is the case of human cytomegalovirus, the replication of which hinges on vMIA (viral mitochondria-localized inhibitor of apoptosis), a virus-encoded protein with a unique, albeit poorly understood antiapoptotic activity by which it binds and recruits Bax to mitochondria. Here we show, via the structure determination of the complex between Bax and a peptide comprising vMIA's Bax-binding domain, that vMIA contacts Bax at a previously unknown regulatory site. Notably, using full-length vMIA, the structure is independently confirmed by assays in human cells that measure Bax subcellular localization and cytochrome c release. Mutants that disrupt key intermolecular interactions disfavor vMIA's mitochondrial recruitment of Bax, and increase cytochrome c release upon apoptosis induction. In a more stringent test, an engineered binding interface that achieves wild-type-like charge complementarity, although in a reversed fashion, recovers wild-type behavior. The structure suggests that by stabilizing key elements in Bax needed to unravel for its MOM insertion and oligomerization, vMIA prevents these important steps in apoptosis.

Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA.,Ma J, Edlich F, Bermejo GA, Norris KL, Youle RJ, Tjandra N Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20901-6. doi:, 10.1073/pnas.1217094110. Epub 2012 Dec 3. PMID:23213219^[7]

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

References

↑ Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609-19. PMID:8358790
↑ Schmitt E, Paquet C, Beauchemin M, Dever-Bertrand J, Bertrand R. Characterization of Bax-sigma, a cell death-inducing isoform of Bax. Biochem Biophys Res Commun. 2000 Apr 21;270(3):868-79. PMID:10772918 doi:http://dx.doi.org/10.1006/bbrc.2000.2537
↑ 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
↑ Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005 Sep;7(9):909-15. Epub 2005 Aug 21. PMID:16113678 doi:http://dx.doi.org/10.1038/ncb1291
↑ Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX activation is initiated at a novel interaction site. Nature. 2008 Oct 23;455(7216):1076-81. PMID:18948948 doi:10.1038/nature07396
↑ Czabotar PE, Lee EF, Thompson GV, Wardak AZ, Fairlie WD, Colman PM. Mutation to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis. J Biol Chem. 2011 Mar 4;286(9):7123-31. Epub 2011 Jan 3. PMID:21199865 doi:10.1074/jbc.M110.161281
↑ Ma J, Edlich F, Bermejo GA, Norris KL, Youle RJ, Tjandra N. Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA. Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20901-6. doi:, 10.1073/pnas.1217094110. Epub 2012 Dec 3. PMID:23213219 doi:http://dx.doi.org/10.1073/pnas.1217094110

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

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OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2lr1"

Categories: Homo sapiens | Human herpesvirus 5 strain AD169 | Large Structures | Ma J

@@ Line 1: / Line 1: @@
 ==Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA==
-<StructureSection load='2lr1' size='340' side='right'caption='[[2lr1]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2lr1' size='340' side='right'caption='[[2lr1]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2lr1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LR1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2lr1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_herpesvirus_5_strain_AD169 Human herpesvirus 5 strain AD169]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LR1 FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1f16|1f16]]</div></td></tr>
+</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=2lr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lr1 OCA], [https://pdbe.org/2lr1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lr1 RCSB], [https://www.ebi.ac.uk/pdbsum/2lr1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lr1 ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BAX, BCL2L4 ([https://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=2lr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lr1 OCA], [https://pdbe.org/2lr1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lr1 RCSB], [https://www.ebi.ac.uk/pdbsum/2lr1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lr1 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/BAX_HUMAN BAX_HUMAN]] Accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor BCL2 or its adenovirus homolog E1B 19k protein. Under stress conditions, undergoes a conformation change that causes translocation to the mitochondrion membrane, leading to the release of cytochrome c that then triggers apoptosis. Promotes activation of CASP3, and thereby apoptosis.<ref>PMID:8358790</ref> <ref>PMID:10772918</ref> <ref>PMID:8521816</ref> <ref>PMID:16113678</ref> <ref>PMID:18948948</ref> <ref>PMID:21199865</ref>  [[https://www.uniprot.org/uniprot/VGLI_HCMVA VGLI_HCMVA]] Isoform vMIA sequesters proapoptotic BAX at the outer mitochondrial membrane and prevents cytochrome c release and subsequent initiation of the proapoptotic cascade. Also provoques a calcium efflux from host endoplasmic reticulum and F-actin cytoskeleton disruption. Participates in the increase of host mitochondrial biogenesis, thus promoting viral replication by efficient use of newly made mitochondria.  Isoform gpUL37 may play a role in escape from the host antiviral response.
+[https://www.uniprot.org/uniprot/BAX_HUMAN BAX_HUMAN] Accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor BCL2 or its adenovirus homolog E1B 19k protein. Under stress conditions, undergoes a conformation change that causes translocation to the mitochondrion membrane, leading to the release of cytochrome c that then triggers apoptosis. Promotes activation of CASP3, and thereby apoptosis.<ref>PMID:8358790</ref> <ref>PMID:10772918</ref> <ref>PMID:8521816</ref> <ref>PMID:16113678</ref> <ref>PMID:18948948</ref> <ref>PMID:21199865</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
+[[Category: Human herpesvirus 5 strain AD169]]
 [[Category: Large Structures]]
-[[Category: Ma, J]]
+[[Category: Ma J]]
-[[Category: Apoptosis-signaling protein complex]]

2lr1

From Proteopedia

Revision as of 11:13, 15 February 2023

Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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