The Polymer Physics of Disordered Protein Assemblies – Emergent Structure and Function

Intrinsically disordered proteins (IDPs), which form over a third of human proteins, challenge the structure-function paradigm because they function without ever folding into a unique three-dimensional structure. A particularly fascinating example of IDP function is the gating mechanism of the nuclear pore complex (NPC). The NPC is a large macromolecular structure that gates nanoscale pores in the nuclear envelope and controls all nucleo-cytoplasmic traffic such as the import of proteins from the cytoplasm and the export of RNA from the nucleus. The NPC forms a highly selective barrier composed of a large number of IDPs that fill the pore and potentially interact with each other and the cargo.

However, despite numerous studies, the actual structure of the complex within the nuclear pore and its mechanism of operation are poorly understood primarily because of the disordered nature of these proteins. I will present our “bottom-up” approach to understanding the higher-order architecture formed by these proteins using coarse-grained simulations and polymer brush theory. Our results indicate that different regions or “blocks” of an individual NPC protein can have distinctly different forms of disorder and properties and our bioinformatic analysis indicates that this appears to be a conserved feature across all of eukarya. Furthermore, this block structure at the individual protein level is critical to the formation of a unique higher-order polymer brush architecture. Our results indicate that there exist transitions between distinct brush morphologies, which can be triggered by the presence of cargo with specific surface properties which points to a novel form of gated transport in operation within the nuclear pore complex. Insights into this system can potentially be applied to the design of bio-mimetic filters that can achieve highly regulated transport across biological or in vitro membranes.

Bio:

Ajay Gopinathan is currently an Associate Professor and Chair of the Physics Graduate Group at UC Merced. He received his Ph.D in Physics in 2003, from the University of Chicago, working under the supervision of Tom Witten on various problems in soft condensed matter physics including crumpling, colloids and polymers. Following this, he was a joint postdoctoral fellow at UCLA and UCSB with Andrea Liu and Phil Pincus working on biopolymers with a focus on actin dynamics. His current research involves using theoretical and computational methods to understand biological transport at the molecular, cellular and multicellular scales. Examples include understanding cooperative behavior in molecular motor-driven intracellular transport; the role of membrane pore geometry and environment in gated transport through nuclear pores; actin based cellular motility; bacterial cell division and collective motility; optimal foraging in groups and swarming in the presence of behavioral heterogeneity and in disordered environments. Honors include the James S. McDonnell Foundation 21^st Century Science Initiative Award, the George E. Brown, Jr. award and the UC Merced Chancellor's award.