Abstract：
:The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X(L). In contrast to Bcl-X(L), however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an alpha-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membrane-inserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Bax-binding function. We found that Delta131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIADelta131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIADelta131-147 suggest that vMIA forms homo-oligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.
journal_name
Oncogenejournal_title
Oncogeneauthors
Pauleau AL,Larochette N,Giordanetto F,Scholz SR,Poncet D,Zamzami N,Goldmacher VS,Kroemer Gdoi
10.1038/sj.onc.1210511subject
Has Abstractpub_date
2007-11-01 00:00:00pages
7067-80issue
50eissn
0950-9232issn
1476-5594pii
1210511journal_volume
26pub_type
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