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Nuclear Pores Balance Speed and Specificity

10/14/2015
Sarah C.P. Williams

How does the nuclear pore complex manage to filter the passage of cargo into the nucleus when its inner lining is composed of a disordered protein? Find out...


Phenylalanyl-glycyl repeat rich nucleoporins (FG Nups) act as a filter for cargo moving into the nucleus. Most molecules that have such high specificity also have large, set structures that take time to fold, but FG Nups seemed to lack a concrete structure. “This was an intellectual challenge,” said David Cowburn, a structural biologist at Albert Einstein College of Medicine and one of the senior authors of a new study appearing in the journal eLife. “It’s been this head-scratcher in terms of how would you keep specificity and at the same time allow a large number of things to quickly go through.”

Transport factors (purple) bind to FG Nups (green) within the nuclear pore complex despite the lack of an overall structure in the FG Nups (1).

With colleagues at Albert Einstein and Rockefeller University, Cowburn used nuclear magnetic resonance (NMR) spectroscopy to probe the structure of the FG Nups both alone and bound to transport factors—intermediate vehicles that help shepherd cargo through the nuclear pore.

“To our surprise, this protein didn’t really seem to have a well-defined structure, at least on a conventional time scale,” said Cowburn.

Instead, while the FG Nups remain highly dynamic—never settling on a single structure—the transport factors, which themselves contain multiple sites that can recognize the FG Nups, bind quickly to one of many binding sites within the nuclear pore. The so-called “fuzzy” flurry of activity, which hasn’t been seen in other pores, is both fast and specific. Having a flexible structure and multiple binding sites for transport factors is key to the unique biochemistry of the FG Nups.

The findings could have implications for developing therapeutics that target the nuclear pore complex—which has been linked to aging—and is also a boon to basic research on the pores. Cowburn and his colleagues plan to study the differences between various transport factors in their interactions with the FG Nups, as well as how cargo being attached to the transport factors changes things.

“What we modeled was the process of the transport factors going through the pore,” said Cowburn. “It’s probably a slightly slower process with cargo.”

Reference

Hough, L.E., Dutta, K., Sparks, S. et al (2015). The molecular mechanism of nuclear transport revealed by atomic scale measurements. eLife 10.7554/eLife.10027