PHILADELPHIA -- Proteins, which form much of the molecular machinery required for life, are the targets of most drug molecules. One third of all proteins are membrane proteins embedded within the cells fatty outer layer. While scientists can easily study the other two-thirds using such tools as antibodies, they have not had such methods to investigate the membrane-embedded portions of proteins.
To probe the secrets of these seemingly inaccessible proteins, researchers at the University of Pennsylvania School of Medicine have designed peptides that are able to bind to specific regions of transmembrane proteins, using computer algorithms, and information from existing protein sequence and structure databases. This study, which appears in the March 30 issue of Science, looks at how the binding of these designed peptides affects the crucial first steps in blood clotting.
"We can now actually interrogate parts of proteins within the membrane," says senior author William F. DeGrado, PhD, Professor of Biochemistry and Biophysics. "We used computer programs to design small proteins called peptides that can bind to only one of a number of closely related membrane proteins."
The researchers targeted two transmembrane proteins called integrins that influence the behavior of platelets, small blood cells important in clotting. One of these, the IIb3 integrin, the most prominent integrin on platelets, is involved in making platelet aggregates, an important first step in the clotting process.
The other integrin, called V3, behaves much like IIb3, in that it causes platelets to stick to certain proteins on the outside of the cell. "We wanted to see if we could differentiate between the two integrins using two different peptides and, in fact, we can," notes co-senior author Joel Bennett, MD, Professor of Medicine, who works with proteins and cells important in clotting.