Solution Structure of the BHRF1 Protein From Epstein-Barr Virus, a Homolog of Human Bcl-2

Huang, Qiulong; Petros, Andrew M.; Virgin, Herbert W.; Fesik, Stephen W.; Olejniczak, Edward T.

doi:10.1016/j.jmb.2003.08.007

Cited by 80 publications

(74 citation statements)

References 36 publications

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“…KSHV BCL-2 was found not to interact with BAX or BAK. 39 BHRF-1 was found not to interact with BAK, BAX, BAD or BIK, 11 though another group found that it interacted with BAK, but not BAX. 20 Our results demonstrate that both proteins do interact with pro-death BCL-2 family proteins, but the interaction pattern is quite selective.…”

Section: Discussionmentioning

confidence: 96%

“…EBV encodes a viral homolog of BCL-2, anti-apoptotic BHRF-1, 10 which has conserved BH1 and BH2 domains homologous to BCL-2. 11 BHRF-1 can inhibit apoptosis induced by a number of death insults including serum depletion, 12 death induced by tumor necrosis factor a and anti-Fas antibody, 13,14 g irradiation, chemotherapeutic drugs, 15,16 deregulated c-myc, 17 granzyme B, 18 Sindbis virus infection 19 and the tumor suppressor protein p53. 20 BHRF-1 is expressed during the productive/lytic replication cycle.…”

mentioning

confidence: 99%

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BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

Flanagan

Letai

2007

Cell Death Differ

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The Epstein-Barr and Kaposi's sarcoma c-herpesviruses (KSHVs) are associated with certain cancers, and encode B-cell leukemia/lymphoma 2 (BCL-2) homologs, BHRF-1 and KSHV BCL-2, respectively. Little is known, however, about the molecular interactions allowing viral BCL-2 homologs to mediate their anti-apoptotic function. Cellular anti-apoptotic proteins, such as BCL-2 and MCL-1, prevent death via selective interactions with pro-death BH3-only proteins. To investigate whether BHRF-1 and KSHV BCL-2 function similarly, we made recombinant BHRF-1 and KSHV BCL-2 proteins. We identified the individual binding patterns for BHRF-1 and KSHV BCL-2 to BH3 domains. These studies surprisingly showed that KSHV BCL-2 is more closely related to MCL-1 than to BCL-2, a result confirmed by sequence analysis. GST-BHRF-1 and GST-KSHV BCL-2 bound BH3-only family proteins from human cells. BHRF-1 protected mammalian cells from growth factor withdrawal, etoposide and adriamycin. We found that both BCL-2 and BHRF-1 sequestered pro-death BH3-only proteins under growth factor-deficient conditions. Finally, we tested the ability of a panel of BH3 peptides to inhibit BHRF-1 and KSHV BCL-2 function in a mitochondrial model of apoptosis. We found that each could be inhibited by the select group of BH3 peptides identified in our binding assay. Our studies define the biochemical interactions underlying BHRF-1 and KSHV BCL-2 anti-apoptotic function, and identify peptides that are prototypic inhibitors of this function.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

Flanagan

Letai

2007

Cell Death Differ

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“…8 However, these data do not explain how mitochondrial BHRF1 can prevent activation of cytoplasmic Bax. BHRF1 has a less prominent hydrophobic groove for binding BH3-only members 32 and despite being an extremely potent suppressor of Bax/Bak activation, it shows a limited selectivity for BH3-only peptides in vitro. 33 Therefore, these data do not exclude BHRF1-mediating a protective effect through additional as yet unidentified targets at the mitochondria.…”

Section: Discussionmentioning

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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“…2A is the alignment of the BH1 sequences of Bcl-xL and BHRF1. Structural studies have suggested that the hydrophobic groove of BHRF1 is inaccessible; however, mutational analysis has indicated the region is important for its function (12,21,22). To test whether the BH1 region of BHRF1 is required for protection, BHRF1 was mutated at residues analogous to those responsible for hydrophilic interactions between Bcl-xL and Bim (1), specifically, L98, G99, and R100.…”

Section: Bhrf1 Protects Cells From Bim-dependent Apoptosis Via Its Bh3mentioning

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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Solution Structure of the BHRF1 Protein From Epstein-Barr Virus, a Homolog of Human Bcl-2

Cited by 80 publications

References 36 publications

BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

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

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

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