In a new opinion article, members of the Schlieker lab explore the idea of a favorable protein folding environment in the Nuclear Pore Complex (NPC) created by the dynamic interplay between Karyopherins and Nucleoporins (FG-Nups). Well-folded soluble proteins are not the only molecules to cross the NPC. Other cargo likely includes nascent polypeptides in their intermediate folding states, proteins with exposed hydrophobic surfaces critical for binding partners, and proteins with extensive disordered regions (IDRs). The textbook model of nucleocytoplasmic transport does not fully account for these species and the process by which they are chaperoned, and perhaps folded, during transport. This process is especially important for our mechanistic understanding of neurological diseases, where there is both an increased level of non-native protein species and a sequestration of Karyopherins and nucleoporins. The Schlieker lab proposes a model in which FG-Nups, known to maintain the permeability barrier of the NPC, can act as a “solvent” for proteins with intrinsically disordered regions or exposed hydrophobic patches, thus counteracting aggregation and providing a favorable environment for folding. Additionally, any sustained interactions by FG-Nups that may trap partially folded or misfolded protein species in the NPC can be outcompeted by Karyopherins and folding intermediates, thereby allowing for rapid passage from the cytoplasm to the nucleus. These highly dynamic and complex interactions between FG-Nups and Karyopherins could provide the optimal folding phase for proteins passing through NPC.
Read more at https://doi.org/10.1016/j.ceb.2024.102407.
Shravani Balaji