Biochemistry, Structural Biology
St. Jude Children's Research Hospital
Dr. Schulman is also a member of the Departments of Structural Biology and Tumor Cell Biology at St. Jude Children's Research Hospital and codirector of the Program in Cancer Genetics, Biochemistry and Cell Biology at the St. Jude Comprehensive Cancer Center.
Mechanisms Underlying Regulation by Ubiquitin-like Protein Conjugation
Science took hold of Brenda Schulman early. She credits outstanding high school math, biology, and chemistry teachers with stimulating her interests in molecular mechanisms underlying biological regulation. While still in high school, Schulman also had a chance to work in a university lab that was exploring how genes are turned on. It was an exciting time in the field, because high-resolution views of regulatory proteins bound to DNA were just becoming available. This gave Schulman an appreciation for how molecular structure and function are linked to achieve biological regulation.
Schulman is still curious about biological structure, and she integrates knowledge of structural biology, biochemistry, cellular biology, and genetics to address a central question in biology: How can cells respond quickly to the changing demands and cues of their environments?
Often, a cell can react most rapidly by tweaking an existing protein, rather than by taking the time to make a new one. In the case of regulatory proteins, this can mean attachment or removal of entire other molecules that in some way change the appearance, and thus function, of the original protein.
She is currently studying how cells employ a protein "accessory" system to reassign, redeploy, or disintegrate other proteins. The set of accessories, called ubiquitin-like proteins (UBLs), carry out vital signaling for immune responses and cell division. Schulman points out, "Just as eyeglasses improve vision, a coat provides warmth, or an umbrella wards off rain, cells use this set of UBLs as accessories that adapt the functions of their 'wearers' as needed in the cell." Several of the UBLs are deregulated in cancer, neurodegenerative diseases, and viral infections.
Schulman studies how the different UBLs are chosen for their specific jobs, and how attachment of a UBL changes a protein's structure and function. Figuring out those differences will help define the roles of various family members and the molecular basis of recognition, and make it easier to develop therapeutic agents.
Schulman has largely solved a central and long-standing question of how UBLs can work in specific ways. A complex series of reactions is catalyzed by a cascade of enzymes called E1, E2, and E3. The enzymes find, prepare, escort, and attach a UBL to its assigned target molecule. The UBL tag triggers a specific cellular activity, such as one of the steps of cell division.
One focus of the Schulman lab has been to follow a UBL, called NEDD8, through the entire process, from being prepared by E1, escorted by E2, and attached to targets by E3. The lab also wanted to know how NEDD8 serves as an accessory to alter function when it is worn by a protein called cullin-RING.
The lab found that cullin-RING's shape changes into an active form when it wears NEDD8. The attachment of NEDD8 transforms cullin-RING into a kind of molecular "valet" that can then attach a different accessory (ubiquitin) onto other proteins to foster a myriad of biochemical reactions. Among its effects, NEDD8 ultimately sets off a cascade of biochemical reactions to eliminate a molecular brake on cell replication. In the absence of this brake, cell replication could get out of control, and if left unchecked, could be associated with cancer.
Schulman plans to study how a family of UBLs is directed to a wide range of molecules, how they perform their own functions as accessories, and how the ubiquitin family regulates the timing of cell division.