We study communication within the cell. Our primary goal is to understand how signals and molecules are transmitted between nucleus and cytoplasm across the nuclear envelope. We are deciphering the mechanism and structure of the cellular machinery that executes these cellular processes.  Malfunctioning of nucleo-cytoplasmic communication leads to a wide range of prominent human diseases, including viral infections, neuromuscular diseases and many more. We use a diverse array of techniques, including structural, cell biological, and genetic methods, to support our quest for exciting and fundamental discoveries in biology.

Transport across the nuclear envelope

Unlike other membranes, the nuclear envelope has only one known transporter for molecular exchange – the Nuclear Pore Complex (NPC). About 2000 NPCs perforate the nuclear envelope in a human cell and the simple question we ask is: How is it structured and how does it fulfill its myriad functions? Over the past decade we have published over a dozen crystal structures of NPC fragments and subcomplexes, which are now being used to assemble the core scaffold of the ~50 MDa complex. We have established that the NPC is structurally and evolutionarily linked to vesicle coats, which helps in deciphering its mode of action. We are now entering a new phase, in which we will ask specific functional questions, based on the structural principles that we have helped to establish.  These questions include transport of specific cargo classes, cell-specific variations of the NPC composition, viral transport, and emerging transport-unrelated topics.

Mechanical linkers traversing the nuclear envelope are necessary to keep the nucleus in a specific location within the cell. A wide variety of genetic diseases are caused by mutations within proteins involved in establishing these bridges. We ask how these bridges are set up and how they are regulated. Using innovative biochemical methods we have established the structural basis for the LINC complex (Sosa et al., 2012), the centerpiece of the mechanical tether. Current projects include the characterization, functionally and structurally, of all elements that contribute to connecting the cytoskeleton with the nucleoskeleton.

Mechanical connection between nucleus and cytoskeleton