4zih

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Crystal Structure of core/latch dimer of Bax in complex with BimBH3miniCrystal Structure of core/latch dimer of Bax in complex with BimBH3mini

Structural highlights

4zih is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
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 BH3-only protein Bim is a potent direct activator of the proapoptotic effector protein Bax, but the structural basis for its activity has remained poorly defined. Here we describe the crystal structure of the BimBH3 peptide bound to BaxDeltaC26 and structure-based mutagenesis studies. Similar to BidBH3, the BimBH3 peptide binds into the cognate surface groove of Bax using the conserved hydrophobic BH3 residues h1-h4. However, the structure and mutagenesis data show that Bim is less reliant compared with Bid on its 'h0' residues for activating Bax and that a single amino-acid difference between Bim and Bid encodes a fivefold difference in Bax-binding potency. Similar to the structures of BidBH3 and BaxBH3 bound to BaxDeltaC21, the structure of the BimBH3 complex with BaxDeltaC displays a cavity surrounded by Bax alpha1, alpha2, alpha5 and alpha8. Our results are consistent with a model in which binding of an activator BH3 domain to the Bax groove initiates separation of its core (alpha2-alpha5) and latch (alpha6-alpha8) domains, enabling its subsequent dimerisation and the permeabilisation of the mitochondrial outer membrane.

Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction.,Robin AY, Krishna Kumar K, Westphal D, Wardak AZ, Thompson GV, Dewson G, Colman PM, Czabotar PE Cell Death Dis. 2015 Jul 9;6:e1809. doi: 10.1038/cddis.2015.141. PMID:26158515[7]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ Robin AY, Krishna Kumar K, Westphal D, Wardak AZ, Thompson GV, Dewson G, Colman PM, Czabotar PE. Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction. Cell Death Dis. 2015 Jul 9;6:e1809. doi: 10.1038/cddis.2015.141. PMID:26158515 doi:http://dx.doi.org/10.1038/cddis.2015.141

4zih, resolution 2.50Å

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