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Latest research by Biochemistry & CAMS-Oxford Institute researchers has uncovered at the molecular level how BIRC6 (a giant ubiquitin ligase) keeps cells alive.

Cell survival and death are a finely balanced act, important for 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. Inhibitor of Apoptosis Proteins (IAPs) are a family of proteins that prevent untimely cell death.

Research led by Dr Paul Elliott (Dept. of Biochemistry) using single particle cryo-EM and detailed biochemical analyses reveals how the giant IAP BIRC6 keeps cells alive through counteracting the function of caspases – enzymes that execute cell death. With help from CAMS-Oxford Institute researchers, Prof Benedikt Kessler and Dr Adán Pinto-Fernandez, they identified that SMAC antagonises this cell guardian function of BIRC6.

It has always been a pleasure to collaborate with Paul Elliott and his team on ubiquitin-related proteomics analysis. This time, we contributed to the deep interactome analysis of BIRC6 and found that SMAC was a key regulator of BIRC6 function. Dr Adán Pinto-Fernandez 

It has been nearly 20 years since BIRC6 was first identified but owing to its large size, technical challenges prevented a detailed structural and biochemical understanding. This work now provides the first characterisation and molecular understanding of BIRC6 function. Crucially, as certain cancers exploit BIRC6 for their own survival, this research illuminating how BIRC6 functions at the molecular level opens new strategies for cancer therapeutics.

This research published in Science opens a path for development of small molecules targeting BIRC6 in cancer cells to restore cell death.

Read the full article here.