Transmembrane proteins can be found in all cells and are required for a multitude of vital cell functions. Many current drugs are designed to target transmembrane proteins, but creating them from scratch had not previously been possible. According to a new study published in the March issue of Science, researchers have now managed to create complex, custom-designed transmembrane proteins.
To do this, the scientists from the University of Washington Institute for Protein Design had to first understand how transmembrane proteins worked. The team used a computer program called Rosetta, which predicts the structure a protein will fold into after it has been synthesized. Understanding a protein’s structure is key to determining its function.
Predicting protein structures within a membrane is particularly challenging due to its non-polar interior and polar exterior. The team was able to overcome this challenge using a method to design proteins so that the polar, hydrophilic residues fit in a way to form polar-polar interactions that can tie the protein together from within.
"Putting together these 'buried hydrogen bond networks' was like putting together a jig-saw puzzle," said David Baker, a University of Washington School of Medicine professor biochemistry and director of the UW Institute of Protein Design.
Using this design method, the researchers were able to manufacture designed transmembrane proteins within bacteria and mammalian cells using as many as 215 amino acids. The proteins were observed to be thermally stable and able to correctly orient themselves within the membrane. Like naturally occurring transmembrane proteins, these designer proteins traverse the membrane several times and assemble into stable multi-protein complexes.
In the future, researchers will be able tlo use this design technique to create transmembrane proteins that perform customized functions.
Image: This illustration shows how four copies of computer-designed transmembrane protein assembled to form a rocket-shaped tetramer with a wide cytoplasmic base that funnels into eight transmembrane helices and which orients correctly in membrane. Image courtesy of the University of Washington Institute for Protein Design.