Understanding tail-anchored proteins
Mitochondria are the sites of cellular energy production. They employ specialised enzymes such as tail-anchored (TA) proteins to ensure good cell metabolism and cellular function. Such TA proteins are usually translated in the cytosol, the cytoplasmic matrix inside any cell. They are then inserted post-translationally into their corresponding membranes through the use of appropriate signalling pathways in the endoplasmic reticulum (ER), the cellular post office.A plethora of TA proteins exist of diverse yet essential function but the mammalian mechanism of protein insertion into membranes has not been elucidated. The EU-funded ′Uncovering the Mammalian Targeting Machinery for Tail Anchored Proteins′ (TA PROTEIN INSERTION) proposal aimed to uncover and characterise this mechanism. Researchers focused on BCL2, an oncogene whose function is to prevent cell death.Scientists performed microscopy analysis of fluorescently tagged proteins in yeast to determine co-localisation with and dependency on other proteins. Spf1, an ER ATPase was shown to affect mitochondrial membrane TA protein insertion by modulating lipid and protein composition. As a result, the inherent differences in membrane composition were found to be the main determinant of determining TA protein integration specificity. Important insight was also generated on how mitochondrial TA proteins change under different stress conditions.Apart from enhancing fundamental knowledge on the mechanisms of localisation and specificity of TA protein insertion, the project findings hold translational impact as well. Given the involvement of BCL2 in cancer, the study outcomes should help uncover new molecular aspects of cancer, and provide new options for diagnosis and therapy.
