Solving the Nuclear Pore Complex

In the spring 2015 issue of this magazine, we wrote about André Hoelz, who is using X-ray crystallography to solve the architecture of one of the most elaborate structures in biology, the nuclear pore complex (“X-ray Vision,” E&S, Vol. 78, No. 1). Recently, a team led by Hoelz, assistant professor of biochemistry at Caltech, reported solving another crucial piece of that puzzle.

The nuclear pore complex (NPC) acts as a cellular gatekeeper that controls molecules trying to enter or exit the nucleus, the heart of eukaryotic cells where, among other things, genetic information is stored. For decades, scientists have been trying to figure out how the NPC can be such an effective gatekeeper—keeping out the cellular riffraff while helping to shuttle certain molecules across the nuclear envelope. This is important at least in part because the NPC is targeted by a number of diseases, including some aggressive forms of leukemia and nervous system disorders. In a paper published in Science Express on August 27, the team reported that they have solved the architecture of the pore’s inner ring, a subcomplex central to the NPC’s ability to serve as a barrier and transport facilitator. Hoelz and colleagues had previously described the atomic structure of the outer rings; now that the architectures of the inner and outer rings of the NPC are known, getting an atomic structure of those combined is “a sprint to the summit,” says Hoelz.

“When I started at Caltech, I thought it might take another 10, 20 years to do this,” he continues. “In the end, we have really only been working on this for four and a half years, and the thing is basically tackled. I want to emphasize that this kind of work is not doable everywhere. The people who worked on this are truly special, talented, and smart; and they worked day and night on this for years.”

Ultimately, Hoelz says he would like to understand how the NPC works in great detail so that he might be able to generate therapies for diseases associated with the dysfunction of the complex. —KF