Extended synaptotagmins (E-Syts): Architecture and dynamics of membrane contact sites revealed

Eukaryotic cells are compartmentalized into membrane-enclosed organelles with defined structure and functions. These organelles are separated from each other, and for a long time it was thought that communication between them is confined to vesicular traffic or to exchange of membrane lipids by cytoplasmic transfer proteins. Recently, however, it has become apparent that organelles hitherto not suspected of being intimate friends can align very closely with each other, forming membrane contact sites (MCSs) of distinct structure and composition. Such sites are now known to play pivotal roles in the exchange of molecules and ions, thus being of considerable functional importance. In particular, the widespread network of the endoplasmic reticulum (ER), origin of most membrane proteins and lipids, forms multiple contacts with a variety of organelles such as mitochondria and the plasma membrane (PM). At ER–PM contacts the membranes are closely aligned, being separated by gaps of only 10–30 nm. Different proteins have been shown to be instrumental for contact formation such as junctophilins, stromal interaction molecule (STIM), tricalbins, and, more recently, a small group of ER membrane proteins termed extended synaptotagmins (E-Syts) (1, 2). The name E-Syts reflects their similarity to synaptotagmins, a family of proteins involved in Ca2+-dependent secretion. Although rapid progress has being made concerning the role of E-Syt domains in establishing ER–PM contacts, information about the architecture of the contact sites has hitherto been lacking. In PNAS, Fernandez-Busnadiego et al. (3) used cryoelectron tomography to close this gap in our understanding.