BioP/IPLS Seminar - Prof. Patrick Lusk (Yale University)

Title: Top-down and bottom-up approaches to mechanisms that establish and protect the nuclear compartment

Abstract: Our lab is interrogating the molecular mechanisms that control the biogenesis, maintenance and function of the nuclear envelope membranes and embedded nuclear pore complexes (NPCs). Disruption of the integrity of the nuclear envelope barrier is associated with many human diseases including cancers and neurodegeneration. By using top-down genetic approaches in model organisms, we have uncovered pathways that surveil the de novo assembly of NPCs through the recruitment of the Endosomal Sorting Complexes Required for Transport (ESCRT), which likely seal off defective nascent pores to protect the nuclear compartment. We discovered that the ESCRT machinery is recruited to nascent NPC assembly sites by well conserved integral inner nuclear membrane proteins of the Lap2-emerin-MAN1 (LEM) family, through a mechanism that we are actively pursuing. Simultaneously, we are using bottom-up nano-engineering approaches to build NPC-mimics with DNA origami. These nuclear pores on DNA (NuPODs) provide an experimental platform to directly investigate how nanopore confinement of the intrinsically disordered “FG” nuclear pore proteins establish the selective filter that controls nuclear-cytoplasmic compartmentalization.