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Samuel Sparks, Ph.D.
Scientist, Silicon Therapeutics
Clark Alumnus, BA ’10, MA ’11
Intrinsic disorder in proteins: Insights into the thermodynamic mechanism underlying rapid and selective translocation through the nuclear pore complex
A central tenet of biology states, a protein’s function depends on a unique three-dimensional structure. It has been well documented that proteins that do not form three dimensional structures or misfold can aggregate into amyloid fibrils, a hallmark of diseases such as Alzheimer’s disease. However, it has recently been appreciated that intrinsically disordered proteins (IDPs) play important functional roles and are abundant in various signaling and regulatory pathways. One example of a group of largely intrinsically disordered proteins are the nuclear pore proteins (Nups) that contain multiple phenylalanine-glycine repeats motifs, termed FG Nups that line the central channel of the nuclear pore complex (NPC). FG Nups form a selective filter that allows rapid translocation of specific molecules known as transport factors (TFs) and their cognate cargo, while simultaneously preventing the passage of non-specific macromolecules. To understand the paradoxically rapid yet selective transport mechanism, a combination of NMR, isothermal titration calorimetry and long time-scale molecular dynamics were used to thermodynamically characterize the multivalent interactions between FG Nups and TFs. A combination of low per-FG motif affinity, dynamic sliding motion along interaction sites and an enthalpy–entropy balance prevents high-avidity allows for fast translocation. The large number of FG motifs promotes frequent FG–TF contacts, resulting in enhanced selectivity. These results underline the importance of functional disorder and further expands our understanding of the mechanisms of interactions involving IDPs.
Seminars are held at 12:15 p.m. on Friday afternoons in Room S122, Arthur M. Sackler Sciences Center. We hope that all who are interested will join us.
LOCATION: Arthur M. Sackler Sciences Center, Room S122