A new Yale study shows that the structures of the three major classes of proteins are surprisingly similar.
By developing a model that predicts protein packing — an important metric in describing proteins — researchers in the physics department determined that soluble proteins, protein-protein complexes and transmembrane proteins have similar packing densities. Before this study, little was known about the structures of transmembrane proteins or how the interiors of the three classes were related. The study was published in the journal Proteins on Feb. 10.
“We had done a lot of good work modeling the cores of soluble proteins,” said Corey O’Hern, the study’s senior author and professor of mechanical engineering and physics. “We then wanted to see if our results could generalize to other protein classes. There are over 100,000 protein crystal structures for soluble proteins, but say, only around 20 structures for transmembrane proteins.”
Proteins are a diverse group of molecules essential for nearly all life processes. One defining aspect of proteins is how they interact with water. Those that interact favorably with water are deemed soluble proteins. Others, however, have portions that cannot interact with water due to the presence of hydrophobic, amino acids. These insoluble segments of proteins often reside in a cell’s membrane and are called transmembrane proteins, which make up almost 30 percent of all human proteins, according to the study.
“Many proteins are inside the cell and thus water-exposed, but some are in the cell membrane, which is a very different environment,” said Jennifer Gaines, a postdoctoral researcher and the study’s lead author. “We wanted to understand if proteins in the membrane are different from proteins inside the cell.”
The cell membrane is composed of proteins, other molecules and a fatty lipid bilayer. Since little was known about the structure and stability of membrane proteins, some groups argued that membrane proteins were more densely packed than soluble proteins, while others argued the opposite, according to the study.
“There had been a lot of controversy in transmembrane proteins because there were not a lot of structures,” O’Hern said. “There were lots of different hypotheses.”
To address the issue, the researchers applied simple models to soluble protein molecules with well-known structures. This step allowed the researchers to determine whether their models actually worked. After confirming the validity of their models in transmembrane proteins, they moved on to the other two protein classes, ultimately discovering that the inside cores of all three classes of proteins are equally well-packed.
“They all have the same packing fraction, which indicates the amount of empty space in the protein and tightness of interactions, and they can all be predicted using our model,” Gaines said.
This finding has many potential implications, especially in protein design. By successfully modeling protein structures, researchers can potentially design new proteins with altered functions. Scientists can then use these new proteins as therapeutics or to model biological processes.
“Now we want to design new transmembrane proteins or find transmembrane proteins with improved capabilities or improved stabilities by making changes to residues,” O’Hern said.
Vikram Shaw | email@example.com