The Vaccinia Virus F1L Protein Interacts with the Proapoptotic Protein Bak and Inhibits Bak Activation

Wasilenko, Shawn; Banadyga, Logan; Bond, David; Barry, Michèle

doi:10.1128/jvi.79.22.14031-14043.2005

Cited by 87 publications

(147 citation statements)

References 61 publications

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“…The nature of this other form of death remains to be determined. In this context, it is interesting to note that, perhaps not coincidentally, another viral antiapoptotic protein from vaccinia, F1L, also binds both Bak and Bim, and the protective capacity of F1L remains in the absence of Bak (34,35).…”

Section: Discussionmentioning

confidence: 99%

The Epstein–Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim

Desbien

Kappler

Marrack

2009

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

The Epstein–Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim

Desbien

Kappler

Marrack

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Although only very weak binding was detected here to the BH3 peptide from Bak, interaction between F1L and Bak in transfected cells has been observed. 15 This might suggest a synergy deriving from the co-localization of Bak and F1L on the mitochondrial membrane, or the importance of regions of Bak and F1L other than the tongue-in-groove components (for example, the membrane anchoring regions), in the interaction. In contrast, we have measured a weak interaction with the Bax BH3, but no association of F1L with Bax in a cell has been reported, other than following detergent activation of Bax.…”

Section: Discussionmentioning

confidence: 99%

“…14 N1L reportedly binds BH3 peptides of Bim, Bak and Bid, 12 and interacts with Bad, Bax and Bid in cells transfected with the N1L gene. 13 In contrast, virus lacking F1L (VVDF1L) results in apoptosis of infected cells in culture, 10,15 suggesting that Figure 5 Novel consensus sequence motif redefining the BH4 domain. The novel BH4 motif is formed by f 1 f 2 X X f 3 f 4 , where X is any amino acid, f is a hydrophobic residue and f 3 is an aromatic residue.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of any apoptotic stimuli, F1L reportedly binds to endogenous Bak but not to pro-survival Bcl-2 family members. 9,15 F1L also inhibits the activation of Bax and its translocation to mitochondria following an apoptotic stimulus, possibly because it interacts with Bim. 16 To elucidate at a molecular level how F1L counters apoptosis, we solved by X-ray crystallography the threedimensional structure of F1L isolated from the modified vaccinia virus Ankara strain (MVA).…”

mentioning

confidence: 99%

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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

et al. 2008

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Apoptosis is an important part of the host's defense mechanism for eliminating invading pathogens. Some viruses express proteins homologous in sequence and function to mammalian pro-survival Bcl-2 proteins. Anti-apoptotic F1L expressed by vaccinia virus is essential for survival of infected cells, but it bears no discernable sequence homology to proteins other than its immediate orthologues in related pox viruses. Here we report that the crystal structure of F1L reveals a Bcl-2-like fold with an unusual N-terminal extension. The protein forms a novel domain-swapped dimer in which the a1 helix is the exchanged domain. Binding studies reveal an atypical BH3-binding profile, with sub-micromolar affinity only for the BH3 peptide of pro-apoptotic Bim and low micromolar affinity for the BH3 peptides of Bak and Bax. This binding interaction is sensitive to F1L mutations within the predicted canonical BH3-binding groove, suggesting parallels between how vaccinia virus F1L and myxoma virus M11L bind BH3 domains. Structural comparison of F1L with other Bcl-2 family members reveals a novel sequence signature that redefines the BH4 domain as a structural motif present in both pro-and anti-apoptotic Bcl-2 members, including viral Bcl-2-like proteins. In higher organisms, programmed cell death (apoptosis) is a prominent feature of the response to viral infection. The central role of the Bcl-2 protein family in maintaining cell survival or driving apoptosis, thereby removing infected, damaged or unwanted cells, is reflected by the expression of sequence, structural and functional orthologues of Bcl-2 by certain viruses. 1 The Bcl-2-related proteins share the presence of one or more of four Bcl-2 homology (BH) domains in their primary sequences and act either to promote cell survival or to counter this. 2 Pro-survival family members such as mammalian Bcl-2, Bcl-x L , Bcl-w, Mcl-1 and A1 block apoptosis until their protective effect is countered by binding of proapoptotic BH3-only proteins, such as Bim, Bad or Noxa. 2,3 Pro-survival Bcl-2 proteins contain multiple BH domains, whereas the distantly related BH3-only proteins contain only the a-helical BH3 domain, which binds a receptor-like groove on the pro-survival proteins, thereby inactivating them. 4,5 Upon activation, pro-apoptotic Bax and Bak, which are essential for apoptosis to proceed, 6 oligomerize to cause organellar damage.The viral Bcl-2-like proteins, including those expressed by adenovirus, Kaposi sarcoma-associated herpesvirus, Epstein-Barr virus (EBV) and g-herpesvirus 68, are all required for successful viral propagation and/or persistence. However, other viruses express anti-apoptotic proteins that are unrelated by sequence to any known cell death regulator. These include the myxoma virus M11L, 7 cytomegalovirus vMIA 8 and vaccinia virus F1L 9 and E3L. 10 Despite the lack of sequence similarity, M11L adopts a Bcl-2-like fold. 11 Moreover, the structure of M11L in complex with the BH3 peptide from Bak revealed that the canonical BH3-binding groove is utilized in...

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“…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.…”

mentioning

confidence: 99%

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

et al. 2008

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Mitochondrial dysfunction mediated by Bax and Bak is a critical step in mammalian cell apoptosis. However, the molecular mechanism of Bax activation remains unknown and has been difficult to investigate due to its rapid and stochastic nature. It is currently unclear whether mitochondria play a passive role in the initiation of apoptosis, remaining unaffected by cell stresses until Bax and Bak are active, or whether they actively participate in Bax/Bak activation. Here, two viral proteins, E1B19K and BHRF1, are examined for their ability to block Bax activation at different steps and thereby reveal the timing of mitochondrial changes during apoptosis. We demonstrate that BHRF1 strongly inhibits Bax activation but not upstream apoptotic signaling events, while E1B19K permits initial stages of Bax activation but prevents the subsequent oligomerization of Bax that is required for mitochondrial dysfunction. In this defined system we show that changes in mitochondrial ultrastructure, characteristic of cells undergoing apoptosis, precede Bax activation and are not blocked by E1B19K and BHRF1. We suggest that the ability of mitochondria to respond to apoptotic stress prior to Bax activation indicates that these organelles may play a direct role in activating Bax.

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The Vaccinia Virus F1L Protein Interacts with the Proapoptotic Protein Bak and Inhibits Bak Activation

Cited by 87 publications

References 61 publications

The Epstein–Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim

The Epstein–Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim

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

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

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