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Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1.


ABSTRACT: Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.

SUBMITTER: Kvansakul M 

PROVIDER: S-EPMC3009601 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1.

Kvansakul Marc M   Wei Andrew H AH   Fletcher Jamie I JI   Willis Simon N SN   Chen Lin L   Roberts Andrew W AW   Huang David C S DC   Colman Peter M PM  

PLoS pathogens 20101223 12


Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression  ...[more]

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