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St. Jude shows how disorderliness in some proteins lets them interact with a diversity of molecules


Discovery of the sequence of events in the binding of p27 to a protein complex is a model for explaining how 30 to 40 percent of the body’s proteins exploit their flexibility in order to do different tasks in the cell

Investigators at St. Jude Children’s Research Hospital have demonstrated for the first time that--contrary to the long-held belief among scientists that proteins must maintain a rigid structure in order to perform an assigned task--many proteins actually exploit disorderliness in their structure to perform a variety of different jobs. The findings of this research appear in the current, online issue of Nature Structural and Molecular Biology.

The St. Jude finding explains how many of the body’s proteins can adapt their structures to the needs of the moment, binding to different molecules depending on the job at hand.

"The potential importance of disorder in the function of some proteins has been discussed by researchers for several years," said Richard W. Kriwacki, PhD, associate member of the St. Jude Department of Structural Biology and senior author of the report. "But until now no one had actually demonstrated how such flexibility allows a protein to interact with different molecules. We’ve taken a big step in understanding the subtle details of a critical biochemical process in the life of the cell."

Previously, other researchers suggested that 30 to 40 percent of the body’s proteins do not rely on a rigid structure to interact with target molecules. In the current study, the St. Jude team verified that idea by showing how a protein called p27 uses two flexible arms to help it bind to a protein complex called Cdk2-cyclin A. This interaction is important because Cdk2-cyclin A is one of the so-called "master timekeepers" of cell division. These timekeepers trigger sequential events leading to the production of new daughter cells. By binding to Cdk2-cyclin A and blocking its activity, p27 disrupts this sequence and prevents the cell from dividing. The importance of p27’s role in regulating cell division is highlighted by findings showing that loss of p27 function is a key contributing factor in several types of cancer.

The researchers demonstrated that the p27 protein resembles a relatively rigid helical (twisted) rod with a wobbly piece of spaghetti hanging off each end. One of the wobbly arms binds to cyclin A, while the other arm binds to Cdk2.

When p27 is by itself in a solution, the arms are loose and disordered. But when p27 encounters Cdk2-cyclin A, one of its arms binds to cyclin A by folding into a rigid shape. After the first arm binds, the center rod settles across the entire Cdk2-cyclin A complex. Finally, the second arm also folds into a rigid shape onto the Cdk2 part of the complex. In this way, proteins such as p27 act as molecular ’staples’ that fasten onto their targets.

"The very act of binding to the Cdk2-cyclin A complex makes the loose, disordered arms of p27 fold up and become rigid," Kriwacki said.

The researchers also discovered how proteins like p27 can identify and bind to complexes with different types of Cdk and cyclin, such as Cdk4-cyclin D--an ability that is critical for them to correctly identify which complexes they are supposed to regulate.

"We discovered that all Cdk molecules look pretty much alike to p27," Kriwacki said. "But a certain part of each type of cyclin is unique. The first flexible arm of p27 recognizes only certain types of cyclin, based on that unique part of the molecule. The first arm binds to this part of the cyclin, and the rest of the p27 follows along."

Using nuclear magnetic resonance spectrometry, which combines radio wave emissions and a powerful magnetic field to determine the structure of proteins suspended in solutions, the team determined the shape of p27 when it was unbound. In order to study the interaction between p27 and Cdk2-cyclin A, researchers in the St. Jude Hartwell Center for Bioinformatics and Biotechnology used a technique called surface plasma resonance. This technique measures the changes in the reflection of light off p27 before and after it binds to Cdk2-cyclin A.

Bonnie Cameron | EurekAlert!
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