Cell survival and death are finely balanced acts, important for the normal development of multicellular organisms. Many cancer cells switch off cell death mechanisms and upregulate proteins that normally prevent unwanted cell death thus ensuring their survival. Inhibitors of Apoptosis Proteins (IAPs) are a family of proteins that prevent untimely cell death.
This research published in Science opens a path for development of small molecules targeting BIRC6 in cancer cells to restore cell death. The study’s lead researcher Dr Paul Elliott from the Deptartment. of Biochemistry used single particle cryo-EM and detailed biochemical analyses to reveal how the giant IAP BIRC6 keeps cells alive by counteracting the function of caspases – enzymes that execute cell death. Along with Prof Benedikt Kessler from the Target Discovery Institute and Dr Adán Pinto-Fernandez from the Chinese Academy of Medical Sciences Oxford Institute (COI) the team uncovered the BIRC6 interactome using cutting-edge proteomics. One identified interactor, SMAC, antagonises this cell guardian function of BIRC6 and this study explains how this is achieved at the molecular level.
On the impact of the findings, Dr Paul Elliott explains, “It’s been nearly 20 years since BIRC6 was first identified as a regulator of cell death but owing to its huge size (nearly 5000 amino acids) technical challenges prevented a detailed structural and biochemical understanding. We now provide the first characterisation and molecular understanding of BIRC6 function. Crucially, as certain cancers exploit BIRC6 for their own survival, our research illuminating how BIRC6 functions at the molecular level opens new strategies for cancer therapeutics. Our work excitingly provides the biochemical and structural framework for these future studies into BIRC6.”