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Publication Abstract from PubMed

Programmed cell death is a tightly controlled process critical for the removal of damaged or infected cells. Pro- and anti-apoptotic proteins of the Bcl-2 family are pivotal mediators of this process. African Swine Fever virus (ASFV) is a large DNA virus, the only member of the Asfarviridae family, and harbors A179L, a putative Bcl-2 like protein. A179L has been shown to bind to several pro-apoptotic Bcl-2 proteins, however the hierarchy of binding and the structural basis for apoptosis inhibition are currently not understood. We systematically evaluated the ability of A179L to bind pro-apoptotic Bcl-2 family members, and show that A179L is the first anti-apoptotic Bcl-2 protein to bind to all major death inducing mammalian Bcl-2 proteins. We then defined the structural basis for apoptosis inhibition of A179L by determining crystal structures of A179L bound to both Bid and Bax BH3 motifs. Our findings provide a mechanistic understanding for the potent anti-apoptotic activity of A179L by identifying it as the first pan pro-death Bcl-2 binder, and serve as a platform for more detailed investigations into the role of A179L during ASFV infection. IMPORTANCE: Numerous viruses have acquired strategies to subvert apoptosis by encoding proteins capable of sequestering pro-apoptotic host proteins. African Swine Fever virus (ASFV), a large DNA virus and the only member of the Asfarviridae family, encodes the protein A179L that functions to prevent apoptosis. We show that A179L is unusual amongst anti-apoptotic Bcl-2 proteins in being able to physically bind to all core death inducing mammalian Bcl-2 proteins. Currently, little is known regarding the molecular interactions between A179L and the pro-apoptotic Bcl-2 members. Using crystal structures of A179L bound to two of the identified pro-apoptotic Bcl-2 proteins, Bid and Bax, we now provide a 3D view of how A179L sequesters host pro-apoptotic proteins, which is crucial for subverting premature host cell apoptosis.

Structural insight into African Swine Fever virus A179L mediated inhibition of apoptosis.,Banjara S, Caria S, Dixon LK, Hinds MG, Kvansakul M J Virol. 2017 Jan 4. pii: JVI.02228-16. doi: 10.1128/JVI.02228-16. PMID:28053104^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.