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UNIGE researchers reveal how two key proteins control cell death, a discovery that could inspire more targeted cancer treatments.
In every organism, the regulation of cell populations is a constant process. This balance relies on a continuous interplay between "guardian" proteins that promote cell survival and "killer" proteins that trigger programmed cell death, known as apoptosis. Any disruption of this balance can lead to diseases such as cancer. In a study published in the Proceedings of the National Academy of Sciences, researchers from the University of Geneva (UNIGE) have, for the first time, observed a key "guardian" protein, Bcl-xL, preventing the action of a "killer" protein, tBid. Until now, treatments targeting this mechanism have often lacked selectivity. By revealing the structure and dynamics of these interacting proteins, the researchers have finally provided a molecular view of apoptosis regulation, paving the way for the design of molecules capable of specifically disrupting this interaction and inducing cell death in cancer cells.
Apoptosis is a finely regulated process in which a network of "killer" proteins can induce cell death and lead to the cell's elimination. Once activated, this network is irreversible; therefore, it must be inhibited early on by "guardian" proteins that block the pro-apoptotic "killer" proteins. Cancer cells often overproduce these guardian proteins, which neutralise the pro-apoptotic proteins and thereby disable one of the body's most effective defence mechanisms. The guardians therefore represent a particularly relevant target for developing new treatments for cancer or degenerative diseases.
"Until now, we were essentially in the dark: we knew that the guardians must stop the killers, but we did not know how. Studying such small and dynamic complexes is difficult, as the interaction occurs exclusively within a membrane environment and capturing flexible proteins is challenging for conventional methods. It was like trying to understand how a helicopter flies without being able to see the moving blades. Now we can see the blades moving relative to the cabin and therefore understand how the helicopter flies", explains Christina Elsner, a post-doctoral researcher in the group of Prof. Enrica Bordignon, in the Department of Physical Chemistry, School of chemistry and biochemistry of the Faculty of Science at UNIGE and co-first author of the study.
A better understanding of the molecular basis of the guardian–killer complex could help guide the development of more precise therapeutic agents.
Towards more selective anticancer drugs
Anticancer therapies targeting the apoptosis control mechanism already exist, but they are not highly selective, as they cannot precisely target cancerous tissues or specific guardian proteins involved. This lack of selectivity is due to the fact that the apoptosis control network is present and active throughout the body. A better understanding of the molecular basis of the guardian–killer complex could help guide the development of more precise therapeutic agents.
In this study, scientists combined electron paramagnetic resonance (EPR) and computer-based molecular simulation to analyze in detail, at the molecular level, how a guardian protein, Bcl-xL, binds to a pro-apoptotic protein, tBid, and inhibits apoptosis at the mitochondrial outer membrane, the outer membrane of our cell's "energy plant". Specifically, the researchers show that Bcl-xL anchors itself to the mitochondrial membrane and sequesters a specific small part of the tBid protein, leaving the rest of tBid flexible. This architecture precisely defines which region of Bcl-xL acts as a "lock" for tBid and which residues are essential for inhibition.
Anton Hanke, doctoral researcher from the group of Prof. Francesco Gervasio in the Department of pharmaceutical sciences at the UNIGE's Faculty of science, and co-first author of the study, explains: "Combining these two methods provides a comprehensive view of the structure and its dynamics. Previously we had only a very partial description of the interaction between Bcl-xL and tBid, lacking a description of the full protein complex and the role lipid membranes play within it. So to speak, we were blind to the context of the interaction limiting our ability to develop drugs targeting this interaction."
These results can guide the design of small molecules capable of either disrupting this interaction to induce apoptosis in cancer cells or stabilizing it to protect cells in diseases where excessive cell death is harmful (e.g. neurodegenerative diseases like Parkinsons), with the goal of developing more selective therapies with fewer side effects.
