The nuclear pore complex (NPC), a massive protein structure that controls the movement of molecules into and out of the cell nucleus, stands as one of the most impressive feats of cellular architecture. Now, researchers at the University of California, Berkeley, have discovered new details about how the NPC functions as a gatekeeper, allowing some molecules to pass through while blocking others.

The findings, published in the journal Nature on January 19, 2022, provide insights into how the NPC helps control gene expression, DNA replication, and other essential cellular processes. They could also lead to new treatments for diseases caused by defects in nuclear transport, such as certain types of cancer and neurodegenerative disorders.

"The NPC is like a bustling city with constant molecular traffic," said Michael Rout, a professor of molecular biology at UC Berkeley and a Howard Hughes Medical Institute investigator who led the research team. "We've discovered how one of the key regulatory mechanisms in the NPC is controlled."

The NPC is a protein complex that spans the nuclear envelope, the double membrane that surrounds the cell nucleus. It is composed of approximately 30 different proteins, called nucleoporins, which come together to form a structure that is roughly cylindrical in shape and about 100 nanometers in diameter.

The NPC has two main functions: to allow certain molecules to pass through the nuclear envelope, and to block others. The molecules that are allowed to pass through the NPC include proteins, nucleic acids, and small molecules such as ions. The molecules that are blocked include large molecules such as viruses and protein aggregates.

The researchers used a variety of techniques to study the NPC, including cryo-electron microscopy (cryo-EM), which allowed them to visualize the NPC in unprecedented detail. They found that the NPC is regulated by a specific protein complex called the RanGTPase cycle. The RanGTPase cycle is a series of molecular events that involves the conversion of a small protein called Ran from a form that is bound to guanine triphosphate (GTP) to a form that is bound to guanine diphosphate (GDP).

The researchers found that the RanGTPase cycle controls the opening and closing of the NPC by regulating the activity of a protein called Nup153. Nup153 is a nucleoporin that is located on the cytoplasmic side of the NPC. It acts as a gatekeeper that blocks the movement of molecules through the NPC when it is bound to RanGDP. When RanGTP is present, Nup153 is released from the NPC, allowing molecules to pass through.

"The RanGTPase cycle is a master regulator of nuclear transport," Rout said. "Our findings provide new insights into how this cycle controls the NPC and how defects in the cycle can lead to disease."