Nanoscale structure and dynamics within nuclear pores and condensates

The National Institute of General Medical Sciences awarded Texas A&M University System Health Science Center $420,657 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859, assistance type Project Grant) to support research on nanoscale structure and dynamics within nuclear pores and condensates.

The funded research examines intrinsically disordered proteins and regions in the proteome, with focus on transport properties of the nuclear pore complex and dynamics of protein condensates formed from the fused in sarcoma protein. The research addresses how intrinsically disordered proteins generate permeability barriers while enabling selective transport, and how condensates maintain dynamic properties while developing regions of immobility and variable confinement over extended aging periods.

Performance occurs in College Station, Texas, with a period of performance from July 1, 2026, through March 31, 2031.

Abstract

While over a third of human proteins form fully folded structures and a small fraction are entirely intrinsically disordered, the majority of proteins in the proteome contain both folded domains and intrinsically disordered regions (idrs). Deciphering the functional properties of structurally dynamic idrs requires understanding structural ensembles rather than a few conformational states, and IT is further complicated by the frequent condensation of intrinsically disordered proteins (idps) into dynamic assemblies of hundreds to millions of molecules. For over 23 years, the PI's laboratory has sought to understand the transport properties of the nuclear pore complex (NPC), which utilizes a network of idps to generate a permeability barrier that simultaneously allows for selective transport. In addition to over 200 intrinsically disordered domains, the NPC permeability barrier contains on the order of a hundred transport receptors, thus providing a complex environment with the potential for functional differences on the nanoscale. For example, the PI's laboratory recently established that both nuclear import and export are confined to the periphery of the pore, seemingly within preferred translocation conduits confined to a single spoke of the 8-fold rotationally symmetric pore scaffold. This represents a stunning confinement within what has long been presumed to be a largely dynamic structure. In a second project, condensates formed from the fused in sarcoma (FUS) protein were shown to remain highly dynamic over a week-long aging period, and yet already within the first day, regions of immobility were observed, intimating a sponge-like structural scaffold that is potentially created by regions of variable percolation. Here to, variable levels of confinement were observed at fast imaging speeds - in this case, distinct biophysical behaviors were observed within a single-component assembly, intimating a dynamic equilibrium. The goal over the next five years is to build on these frameworks using a range of three-dimensional (3D) super-resolution imaging and single particle tracking tools to understand the structural and functional properties of the IDP assemblies within the NPC permeability barrier and FUS condensates. In the case of the NPC, the focus will be on understanding whether and how different cargo complexes access and migrate through different regions of the pore, and how different components are distributed throughout the permeability barrier. In the case of FUS condensates, the focus will be on obtaining a more complete picture of structural heterogeneity and structural motifs within more complex condensates with the expectation that the conditions that lead to solidified aggregates will be more clearly defined. The proposed research program seeks to apply multiple powerful and innovative imaging and reporting tools that have already been developed, though IT is also expected that novel strategies will emerge. These studies will yield an improved structural and mechanistic understanding of IDP assemblies on the nanometer and millisecond scales, which are necessary to develop therapeutic strategies to combat human diseases linked to nucleocytoplasmic transport defects and various protein aggregates.