2lr1

Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA

spinqualitylabelsall models 2lr1, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2lr1 is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 1f16 Gene: BAX, BCL2L4 (HUMAN) 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. [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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also B-cell lymphoma proteins 3D structures

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