Scientists identify potential cancer drug development target

Friday, November 4, 2011 12:06 PM
Research led by St. Jude Children's Research Hospital scientists has identified an unexpected mechanism facilitating some protein interactions that are the
workhorses of cells and, in the process, identified a potential new cancer
drug development target.
 
The discovery involves a chemical known as an acetyl group. An estimated
85% of human proteins have this chemical added to the amino acid at
one end of the protein. The addition comes in a process known as
N-terminal acetylation. N-terminal acetylation occurs shortly after
proteins are assembled. Although it has long been known that proteins are
N-terminally acetylated, until now it was unknown how such acetylation
could serve specific functions.
 
The findings came from scientists studying a system cells use to regulate the fate and function of proteins. The researchers showed that much like a key must fit precisely to work a lock, the acetylated end of one enzyme fits perfectly into a deep pocket on the surface of another protein. The connection helps accelerate the activity of a protein complex that is involved in regulating cell division and that has been linked to cancer. The findings have potential implications for drug discovery and for understanding basic mechanisms governing the interaction of possibly thousands of proteins, said the study's senior author, Brenda Schulman, Ph.D., a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute investigator.
 
"The work presents a major new concept in protein-protein interactions," she said. "This raises the question of whether similar 'keys' on thousands of different proteins also unlock doors to allow them to function."
 
The research offers the first view of how N-terminal acetylation mediates protein interactions, bringing proteins together to do the work of cells.
 
The pocket where N-terminally acetylated proteins bind may also be a good target for small molecules designed to block protein interactions that lead to many diseases, including cancers, Schulman said.
 
Schulman and her colleagues discovered the pivotal role N-terminal acetylation plays while studying interactions between the proteins Ubc12 and Dcn1. Other researchers have identified human Dcn1 as an oncogene that promotes some squamous cell head, neck and lung cancers.
 
The focus of the current study was the role the enzymes played in regulating activity of another complex, known as cullin-RING. The cullin-RING complex is the command center of a tagging system that cells use to modify a protein's function or to mark a protein for degradation.

The cullin-RING targeted proteins include those that control such important biological processes as cell division and the immune response.
 
Dcn1 is bound to the cullin protein. In previous studies, Schulman and her
colleagues showed that in yeast the Ubc12 and Dcn1 interaction led Ubc12
to transfer its cargo, a protein called NEDD8, to cullin. That step
dramatically accelerated the activity of cullin-RING.
 
But a major question was how human Dcn1 and Ubc12 interact. The
breakthrough came when the researchers realized that Ubc12 is among the 35
to 50% of proteins in which methionine is the amino acid involved
in N-terminal acetylation. The investigators used a variety of laboratory
techniques to demonstrate that the acetylated methionine of Ubc12 was
essential to the Ubc12-Dcn1 interaction. Evidence included an X-ray image
that shows Ubc12's acetyl-methionine buried in a pocket on the surface of
Dcn1.
 
"The size and shape of the pocket indicate it might be a completely new
route to generating small- molecule inhibitors," Schulman said.
Not only does Ubc12's acetylated tail fit perfectly into the pocket, but acetylation solved another problem that would have made the interaction of Ubc12 and Dcn1 difficult. Without acetylation, Ubc12 and the Dcn1 pocket would repel each other much like oil and water. Acetylation neutralizes the charge on Ubc12, allowing the interaction to occur, Schulman said.
Share:          
CWWeekly

April 20

Christie Clinic, PMG Research's 12th clinical research site, expands its geographic reach north to Illinois

Clinipace acquires Accovion to expand European presence, following an infusion of equity that could lead to more deals

Already a subscriber?
Log in to your digital subscription.

Subscribe to CWWeekly.

The CenterWatch Monthly

April

PSI, INC Research, Chiltern best with sites
Strategic outsourcing prioritizing, improving site relationships

Regulatory compliance an increasing burden on sites
Increased staff time, materials, storage eroding site operating profit

Already a subscriber?
Log in to your digital subscription.

Purchase the March issue.

Subscribe to
The CenterWatch Monthly.

The CenterWatch Monthly

March

Novo Nordisk, Takeda, Servier, Celgene among top sponsors
New gains seen from patient- and site-centric initiatives

Patient reported outcomes take center stage
FDA combining PROs, clinical outcomes in its approval decisions

Already a subscriber?
Log in to your digital subscription.

Purchase the February issue.

Subscribe to
The CenterWatch Monthly.

JobWatch centerwatch.com/jobwatch

Featured Jobs