Programmed cell death is a fundamental process of human biology: Too much cell death is associated with degenerative diseases while too little is a hallmark of cancer. The program relies on a family of proteins that act to regulate mitochondrial membrane integrity. These Bcl-2 family proteins are synthesized in the endoplasmic reticulum (ER) and then translocated to mitochondria from the cytosol. How do they insert into and act in mitochondrial membranes? Using a combination of nuclear magnetic resonance spectroscopy, molecular dynamics simulations, and isothermal titration calorimetry, we show the effect of the membrane environment on the conformation, dynamics, and activity of the cyto-protective protein Bcl-xL. The resulting biophysical insights have important implications for Bcl-xL and the greater Bcl-2 protein family.

The cover image for the October 6 issue of the Biophysical Journal is an artistic rendering of Bcl-xL in its functional, membrane-inserted state, and illustrates the key role of magnetic resonance spectroscopy in probing individual protein sites. Each resonance peak (yellow contour) represents an amide site from a single amino acid in the protein sequence, and acts as a reporter of protein conformation, dynamics, and interactions with its physico-chemical environment. This fundamental biophysical tool is useful for probing a multitude of molecular mechanisms active in biology, extending beyond programmed cell death.

The cover was inspired by the aesthetic appeal of scientific research results. The image was composed with Pymol and Adobe software. The use of complementary colors reflects the importance of complementary approaches in biophysical research. Additional images and research stories are available at https://www.marassilab.org/.

- Pavel Ryzhov, Ye Tian, Yong Yao, Andrey Bobkov, Wonpil Im, Francesca Marassi