2LR1

Structural Mechanism for Bax Inhibition by Cytomegalovirus Protein vMIA

Summary for 2LR1

• Entry DOI: 10.2210/pdb2lr1/pdb
• Related: 1F16
• NMR Information: BMRB: 18340
• Descriptor: Apoptosis regulator BAX, Immediate early glycoprotein (2 entities in total)
• Functional Keywords: apoptosis-signaling protein complex, apoptosis/signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Alpha: Mitochondrion membrane; Single-pass membrane protein. Isoform Beta: Cytoplasm. Isoform Gamma: Cytoplasm. Isoform Delta: Cytoplasm : Q07812; Isoform gpUL37: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Isoform vMIA: Host mitochondrion membrane ; Single-pass membrane protein . Isoform pUL37m: Host mitochondrion membrane ; Single-pass membrane protein : P16778
• Total number of polymer chains: 2
• Total formula weight: 23936.64

Authors

Ma, J. (deposition date: 2012-03-20, release date: 2012-12-05, Last modification date: 2024-05-01)

Primary citation

Ma, J.,Edlich, F.,Bermejo, G.A.,Norris, K.L.,Youle, R.J.,Tjandra, N.
Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA.
Proc.Natl.Acad.Sci.USA, 109:20901-20906, 2012

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.

PubMed: 23213219
DOI: 10.1073/pnas.1217094110

Experimental method

SOLUTION NMR