A class of proteins known as TMEM16 scramblases permit rearrangement of lipids in the cell membrane chiefly by thinning the membrane, according to a new model by Weill Cornell Medicine investigators. The model, based on the highest-resolution images to date of a TMEM16 scramblase, challenges the prevailing theory of how these proteins play their fundamental role in biology and could lead to the first scramblase-targeted pharmaceuticals. Scramblase proteins reside in the outer membranes of virtually all eukaryotic cells and can disorganize—scramble—the normal arrangement of fat-related lipid molecules that constitute the membranes. This disruption of the normal membrane structure is a necessary part of many important biological events including blood coagulation, membrane repair and apoptosis, the programmed death of damaged cells. Dysfunctions of TMEM16 scramblases have been linked to blood and bone disorders, lower sperm motility, cancers and movement disorders, among other conditions. The researchers, whose findings were reported May 11 in Nature Communications, used cryogenic electron microscopy (cryo-EM) to image the structure of a TMEM16 scramblase at near-atomic-scale resolution in a membrane-like environment. The image data suggested strongly that what had been the consensus model of how these scramblases work needs to be revised. “We’re proposing that the TMEM16 scramblase protein works not by interacting directly with specific lipids, but instead by mechanically altering the structure of the membrane, making it generally very thin and disordered,” said Dr. Alessio Accardi, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. The first authors of the study were Dr. Maria Falzone, a PhD candidate in the Accardi lab during the study, and Dr. Zhang Feng, a postdoctoral associate in the Accardi lab. The outer membrane of a cell is composed of two tightly ordered layers of lipid molecules, where the outer and inner layers are…