A Structural Viral Mimic of Prosurvival Bcl-2: A Pivotal Role for Sequestering Proapoptotic Bax and Bak

Abstract

Many viruses express antiapoptotic proteins to counter host defense mechanisms that would otherwise trigger the rapid clearance of infected cells. For example, adenoviruses and some gamma-herpesviruses express homologs of prosurvival Bcl-2 to subvert the host's apoptotic machinery. Myxoma virus, a double-stranded DNA virus of the pox family, harbors antiapoptotic M11L, its virulence factor. Analysis of its three-dimensional structure reveals that despite lacking any primary sequence similarity to Bcl-2, it adopts a virtually identical protein fold. This allows it to associate with BH3 domains, especially those of Bax and Bak. We found that M11L acts primarily by sequestering Bax and Bak, thereby blocking the killing action of these essential cell-death mediators. These findings expand the family of protein sequences that act like Bcl-2 to block apoptosis and support the conclusion that the prosurvival action of these proteins critically depends on their ability to bind and antagonize Bax and/or Bak.

Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands

“…A similar conundrum confronted the explanation for BH3 binding to M11L, but was resolved by a crystal structure of M11L bound to the Bak BH3 domain, supported by mutagenesis and functional analysis. 11 Our mutagenesis studies of the Bim BH3 peptide and F1L, and the associated binding data, support a model in which F1L acts as a receptor for the BH3 domain of the BH3-only protein Bim. The inconsequential effect of the D67A mutation in Bim on this interaction suggests that D67 in Bim may be adjacent to V141 of F1L in the complex.…”

“…11 Moreover, the structure of M11L in complex with the BH3 peptide from Bak revealed that the canonical BH3-binding groove is utilized in this interaction, and tests of M11L mutants showed that its anti-apoptotic action relies on binding to Bak and/or Bax, less so to BH3-only proteins. 11 The vaccinia virus N1L protein also displays a Bcl-2-like fold, 12,13 even though, like myxoma virus M11L, its sequence does not resemble that of Bcl-2. Vaccinia virus lacking N1L replicate normally in cell culture, but are attenuated in animal models.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…71,72 In addition, some viruses encode proteins that share structural and functional similarities with host molecules, such as herpes and myxoma viruses, that mimic anti-apoptotic protein BCL-2 to prolong viral replication before the initiation of hostprogrammed cell death. 73 Not surprisingly, pathogens including bacteria, viruses, fungi and oomycetes also exploit the host's phospholipid code for a variety of functions during an infection (Table 1).…”

Viral pro-survival proteins block separate stages in Bax activation but changes in mitochondrial ultrastructure still occur

“…11 Others, such as adenovirus E1B19K, vaccinia virus F1L, human cytomegalovirus vMIA and myxoma virus M11L, share very low or no sequence homology with Bcl-2 proteins, but are nevertheless able to directly target and inhibit Bax and Bak oligomerization. [12][13][14][15][16][17] M11L has structural homology to Bcl-2 proteins despite a lack of sequence homology 18 but structures are not yet available for other viral inhibitors of Bax/Bak. E1B19K is particularly interesting since it blocks apoptosis in infected cells by binding Bax and Bak, preventing their oligomerization and association.…”