2LR1

Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 500 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the lowest energy 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA.

Ma, J.Edlich, F.Bermejo, G.A.Norris, K.L.Youle, R.J.Tjandra, N.

(2012) Proc Natl Acad Sci U S A 109: 20901-20906

  • DOI: https://doi.org/10.1073/pnas.1217094110
  • Primary Citation of Related Structures:  
    2LR1

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Apoptosis regulator BAX192Homo sapiensMutation(s): 0 
Gene Names: BAXBCL2L4
UniProt & NIH Common Fund Data Resources
Find proteins for Q07812 (Homo sapiens)
Explore Q07812 
Go to UniProtKB:  Q07812
PHAROS:  Q07812
GTEx:  ENSG00000087088 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07812
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Immediate early glycoprotein21Human herpesvirus 5 strain AD169Mutation(s): 0 
UniProt
Find proteins for P16778 (Human cytomegalovirus (strain AD169))
Explore P16778 
Go to UniProtKB:  P16778
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP16778
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 500 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the lowest energy 

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2012-12-05 
  • Deposition Author(s): Ma, J.

Revision History  (Full details and data files)

  • Version 1.0: 2012-12-05
    Type: Initial release
  • Version 1.1: 2013-01-16
    Changes: Database references
  • Version 1.2: 2017-02-22
    Changes: Other
  • Version 1.3: 2024-05-01
    Changes: Data collection, Database references