St. Jude researchers decipher structure, activity of enzyme key to biochemical pathways of life

Finding how E1 enzyme juggles three jobs should lead to critical insights into the control of cellular functions at the heart of health and disease

Scientists at St. Jude Children’s Research Hospital have discovered how a single enzyme called E1 performs a rapid-fire, three-part chemical makeover of a protein that helps control some of the most fundamental biochemical processes of the human cell. The enzyme uses two different parts of its own structure to juggle four different molecules as it completes three different reactions.

This rare ability of a single enzyme to carry out three different chemical reactions by itself is at the heart of the role E1 plays in modifying NEDD8, which is part of a family of proteins called ubiquitin-like proteins. E1 proteins are a family of molecules called activating enzymes.

These enzymes coordinate the activity of different ubiquitin-like proteins.

The cell uses ubiquitin-like proteins such as NEDD8 to trigger special molecules that act as on switches for a variety of biochemical pathways, according to Brenda Schulman, Ph.D., an assistant member of the St. Jude Departments of Structural Biology, Genetics and Tumor Cell Biology.

The pathways switched on by ubiquitin-like proteins include vital activities, such as immune responses and cell division, she said. Schulman is the senior author of a report appearing in the March 20 issue of Nature on the structure and function of the E1 activating enzyme for NEDD8.

“The cell uses E1 activating enzymes to keep a tight rein on all of the various biochemical pathways it must activate,” Schulman said. “Otherwise the cell would be chaotic and wouldn’t be able to perform the tasks it is supposed to do in the body.”

Each type of E1 activating enzyme coordinates a specific function to make sure it occurs at precisely the right time, she says.

The complex series of reactions that control each function begins when a specific E1 activating enzyme combines an ubiquitin-like protein such as NEDD8 to an “escort” molecule.

The escort brings the ubiquitin-like protein to its pre-assigned target molecule. When the ubiquitin-like protein chemically modifies this molecule, the molecule triggers a specific cellular activity, such as cell division.

The discovery of the structure of the E1 activating enzyme for NEDD8 helps explain the critical steps by which E1 links NEDD8 to its E2 escort.

“Now that we know exactly what the E1 for NEDD8 looks like and how it works, we can start to understand how the cell controls its extraordinarily complex command and control systems,” Schulman said. “We’ll start to understand how the cell gets through the day doing its jobs and keeping us healthy–or making us ill when its command and control systems get disrupted.”

For example, the influenza virus hijacks one of the ubiquitin-like proteins so it does not undergo its normal activation by an E1 enzyme.

This hijacking helps the virus hide from the surveillance system set up by the immune system to track infections.

“The more we learn about how these pathways are controlled, the more likely we’ll understand how to fix them when they get disrupted and cause a wide variety of diseases,” Schulman said.

Schulman and her colleagues obtained the information that let them create a picture of the E1 structure using a technique called X-ray crystallography. In this technique, the proteins are first crystallized to immobilize them, and then X-rays are directed at the protein crystal.

The pattern formed by the x-rays as they bounce off the protein crystal is then translated into a picture of the molecule.

Other authors of the paper include Helen Walden, Ph.D. and Michael S. Podgorski, both of St. Jude.

The work was supported by ALSAC, the National Cancer Institute Cancer Center (CORE) and a Pew Scholar in Biomedical Science Award to ’Schulman.

St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children’s Research Hospital. Families without insurance are never asked to pay. For more information, please visit http://.