Lipid scrambling: New players, new questions, new opportunities

Nearly a quarter of the proteins encoded in most organisms are transmembrane proteins. Contrary to textbook description, many feature a hydrophilic groove which is laterally exposed to the hydrophobic region of the lipid membrane. This cavity is stabilized by neighboring lipid headgroups that sink deep into the membrane and consequently move bidirectionally from one leaflet to the other, in a process nicknamed lipid 'scrambling.' These proteins, called scramblases, have been reported to serve in many cellular functions, ranging from lipid redistribution during organelle growth to cellular apoptosis. Despite their importance, the identity of most scramblases has remained a mystery for many years. In the last few years, in silico techniques have accelerated the discovery of dozens of new scramblases. Nonetheless, together with these discoveries, key questions have emerged. In this review, we highlight some open questions in this emerging field and showcase how modern computational techniques can help addressing them.