Deconstructed ‘death receptors’ suggest new ways to tackle cancer, autoimmune disease

death receptors apoptosis cancer autoimmune
The 3-D structure of the Fas death receptor’s transmembrane region, consisting of three tightly packed helices shown here from three angles. Cancer-causing mutations deform this structure, preventing “time to die” signals from passing through. (Fu Q; et al. Molecular Cell, Feb. 5, 2016).

Programmed cell death, or apoptosis, helps keep us healthy by ensuring that excess or potentially dangerous cells self-destruct. One way cells know it’s time to die is through signals received by so-called death receptors that stud cells’ surfaces. When these signals go awry, the result can be cancer (uncontrolled cell growth) or autoimmune disease (cells self-destructing too readily).

Researchers at Harvard Medical School (HMS) and the Program in Cellular and Molecular Medicine at Boston Children’s Hospital deconstructed a death receptor called Fas to learn more about its workings, using nuclear magnetic resonance (NMR) spectroscopy to reveal its structure.

They found that for immune cells to hear the “time to die” signal, a portion of Fas called the transmembrane region must coil into an intricate three-part formation, allowing the signal to pass into the cell. The NMR imaging also revealed that the amino acid proline is critical for the formation’s stability. Cancer-causing mutations in the transmembrane region (one of them affecting proline itself) deformed this delicate structure and prevented signals from passing through.

This better understanding of the Fas death receptor, published last week in Molecular Cell, could lead to new approaches that bypass Fas to encourage apoptosis in cancer or, conversely, inhibit Fas in autoimmune disease.

Read more on HMS’s news site.