"The paper marks an advance in our understanding of how cells sort molecules that are to be sent to different places inside the cell," said principal investigator Ian G. Macara, professor of pharmacology at the U.Va. Markey Center for Cell Signaling.
"We call the molecules that are being moved around the cell 'cargo,' and each type of cargo has a Zip code attached that determines the address within the cell to which it must be delivered. We study proteins called 'importins,' which are like trucks that carry the cargo into the center of the cell, the nucleus," he said. "We have discovered a new component of one of these trucks that helps load the cargo, and ensures correct delivery. It may also help the truck distinguish among different nuclear entry codes."
The nucleus of a cell is surrounded by a wall that separates the DNA from the rest of the cell. This wall contains thousands of tunnels, called pores, through which the trucks and their cargo travel. Millions of cargo molecules are carried in and out of each nucleus every minute. This heavy traffic of proteins through the wall occurs in every living organism except bacteria.
Understanding the details of how things get in and out of the nucleus is important, Macara said, because viruses such as HIV have stolen the cargo codes and use the trucks to move their components in and out of the nucleus. This allows them to take control of the cell and to replicate within it.
The U.Va. study found that the new component, called Npap60 (nuclear pore-associated protein) attaches to its truck in three different ways, depending on whether the truck is in the cytoplasm picking up cargo, en route inside the tunnel or in the nucleus making its delivery.
"It's something no one would notice unless they take this component apart and look at how each small bit works," Macara said. "If you just asked how the intact Npap60 binds to its truck, it would always look the same, but by looking more closely you see this amazing switch mechanism. The way it works is very unusual, and is contrary to what scientists previously thought was the function of Npap60. Now we want to know if it helps the truck select different types of cargo."
How such selection might take place is the next step in the research by Macara and Mark E. Lindsay, a medical and doctoral degree student at the U.Va. School of Medicine who initiated and led the study.
Cargo entry into the nucleus is used for many different functions of living organisms," Macara said. "Proteins activate genes by entering the nucleus, and viruses must enter the nucleus in order to replicate. If we know how importins recognize nuclear entry codes, we may find out the mechanism for allowing or barring entry of viruses or proteins that switch on genes to cause disease."
The study was funded by the National Institutes of Health.