Weill Cornell Team Reveals How TMEM16F Scramblase Works

Weill Cornell Medicine investigators have mapped the detailed workings of TMEM16F, a cell membrane scramblase with essential roles in all animals. Their findings may guide future therapies for blood coagulation disorders, cancers, and other conditions in which the TMEM16F scramblase functions abnormally. 

TMEM16F is a scramblase, meaning it alters the normal layered arrangement of lipid molecules in the cell membrane, and it also functions as an ion channel that allows small charged molecules such as potassium or chloride ions to pass through the membrane. Despite its broad importance, scientists had until now been unable to capture high‑resolution images of the functioning protein.

In the study, published in Nature Structural and Molecular Biology, the researchers embedded TMEM16F in artificial liposomes, tiny lipid capsules with layered membranes similar to those of real cells. This approach allowed them to visualize both the active and inactive conformations of the scramblase at near‑atomic resolution. Senior author Dr. Alessio Accardi said the results pave the way for targeted discovery of inhibitors or activators of this scramblase, which could be useful, for example, in treating coagulation‑related disorders.

TMEM16F’s rearrangement of membrane lipids helps platelet cells clump together so blood can coagulate, and mutations in the scramblase underlie a hemophilia‑like bleeding disorder called Scott Syndrome. The protein also contributes to placenta formation during pregnancy, bone development, and immune functions, and it is altered or exploited in various cancers and infections.

The team found that liposome membranes closely mimicked the natural membrane environment and that TMEM16F remained functionally active in that setting. Using elevated calcium levels to trigger the scramblase, they applied low‑temperature electron microscopy and computer modeling to compare normal and mutated forms of the protein. They observed that elements of TMEM16F rotate into an X‑shaped configuration that opens a pore or groove in the membrane.

Ions move through the inside of TMEM16F while lipids move along the outside, and this arrangement locally thins the membrane, enabling rapid lipid scrambling. Dr. Accardi noted that this mechanism is markedly different from earlier models of related scramblases. With these detailed structural views in hand, the researchers can now design drug molecules that specifically target the active states of TMEM16F, such as activators for bleeding disorders or inhibitors for anticoagulant applications.