Because it lacks a predictable structure, an FG Nup (green), a component of the nuclear pore complex, can interact quickly with a transport factor (purple) bound to large cargo. [Laboratory of Cellular and Structural Biology, Rockefeller University]
Because it lacks a predictable structure, an FG Nup (green), a component of the nuclear pore complex, can interact quickly with a transport factor (purple) bound to large cargo. [Laboratory of Cellular and Structural Biology, Rockefeller University]

Nuclear pore complexes, the gimlet-eyed gatekeepers of the nucleus, combine two seemingly incongruous properties: selectivity and speed. Selectivity ordinarily depends on large, lumbering proteins that maintain definite shapes. Yet the selectivity demonstrated by nuclear pores is not only stringent, restricting the passage of potentially harmful macromolecules, but is also remarkably quick. Once a macromolecule is bound to a transport factor, the passage of cargo through the nuclear membrane takes just a few milliseconds.

Such speed may be incompatible with the sort of recognition mechanism that is typical of large, rigid molecules. As it turns out, in the case of nuclear transport, recognition depends on something quite different—floppiness. The nuclear pore contains intrinsically disordered proteins that form a dense mesh. This mesh normally prevents the passage of large molecules, yet because it is made of proteins that stay loose and string-like, it is also highly dynamic.

The floppy proteins contain phenylalanyl-glycyl (FG)-rich repeats, and these repeats line the nuclear pore and interact with transport factors, large proteins that ferry molecular cargo across the nuclear membrane. FG repeats lack a predictable structure and move quickly. In a flurry of interactions, they attach to and release certain binding sites with which transport proteins are pockmarked. All this activity—called fuzzy activity—is both fast and specific.

These results were generated by scientists who followed the fuzzy action with NMR spectroscopy. This technique enabled the scientists, who were affiliated with Rockefeller University, Albert Einstein College of Medicine, and the New York Structural Biology Center, to gather atomic-scale information on the behavior of FGs and the interactions with transport factors (TFs).

The scientists, led by Rockefeller’s Michael P. Rout, Ph.D., and Albert Einstein’s David Cowburn, Ph.D., published their findings September 15 in eLife, in an article entitled, “The molecular mechanism of nuclear transport revealed by atomic scale measurements.”

“We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment,” wrote the authors. “Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the [nuclear pore complex].”

“We observed that there is minimal creation of a static well-ordered structure in complexes of FG Nups and transport factors,” said Dr. Cowburn. “Our observations are, we propose, the first case where the 'fuzzy' property of an interaction is a key part of its actual biological function.”

The team hopes that their discovery will lead to detailed characterizations of nuclear transport pathways and a better understanding of nuclear pore function. Ultimately, a better understanding of how the nuclear pore complex works will not only provide new insight into the basic biology of cells, but also have implications for health and disease.








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