F1L

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bak is a member of the executioner-faction of the Bcl-2 protein family. Its function is normally antagonised by the Bcl-2 homologue Mcl-1, and Mcl-1 function is itself antagonised by the so-called BH3-only proteins that transmit various stress stimuli to the apoptotic machinery. M11L and F1L are viral inhibitors of programmed cell death (apoptosis) from Myxoma virus and Vaccinia virus, respectively. Both M11L and F1L appear to act on the mitochondrial pathway to apoptosis by targeting Bak. Despite the ability of M11L and F1L to bind Bak, neither has a detectable sequence homology to the Bcl-2 family of proteins or indeed to any other protein of known 3-D structure. Viruses are dependent on their host to ensure their own proliferation and propagation. Programmed cell death or apoptosis is an important mechanism employed by host immune systems to combat viral infections and prevent their spread. Viruses employ several strategies to counter host immune responses, including expression of viral pro-survival proteins that inhibit apoptosis of host cells. M11L and F1L are viral proteins that potently inhibit apoptosis by interfering with the mitochondrial-dependent intrinsic pathway of apoptosis by targeting Bak. Over-expression of M11L is sufficient to prevent apoptosis after suitable death stimuli by inhibiting MMP. We have obtained crystals for M11L both in the presence and absence of a human Bak 26-mer peptide, as well as crystals for F1L. Structural studies of the molecular control of Bak will inform efforts to discover drugs that can, on the one hand, bypass dysfunctional upstream cues that prevent many cancer cells from entering apoptosis, or, on the other, prevent untimely apoptosis associated with some degenerative disorders.