Researchers examined the protein structures, about 30% of the proteins encoded by the human genome are membrane proteins that span the cell membrane so they can facilitate communication between cells and their environment. These molecules are critical for learning, seeing, and sensing odors, among many other functions. The study was published in the Proceedings of the National Academy of Sciences.
Despite the prevalence of these proteins, scientists have had difficulty studying their structures and functions because the membrane-bound portions are very hydrophobic, so they cannot be dissolved in water. This makes it much harder to do structural analyses, such as X-ray crystallography.
In an advance that could make it easier to perform this type of structural study, MIT researchers have developed a way to make these proteins water-soluble by swapping some of their hydrophobic amino acids for hydrophilic ones.
Of the approximately 8,000 known membrane proteins found in human cells, scientists have discovered structures for about 50. They are widely viewed as very difficult to work with because once they are extracted from the cell membrane, they only maintain their structure if they are suspended in a detergent, which mimics the hydrophobic environment of the cell membrane.
The key idea that allowed Zhang to develop the code is the fact that a handful of hydrophobic amino acids have very similar structures to some hydrophilic amino acids.
Another important factor is that none of these amino acids are charged, so swapping them appears to have a minimal effect on the overall protein structure. Isoleucine and threonine are so similar that ribosomes, the cell structures that assemble proteins.
The researchers call their code the QTY code, after the three letters that represent glutamine, threonine, and tyrosine, respectively. In their earliest efforts to implement this code, the researchers substituted only a small fraction of the hydrophobic amino acids embedded in the membrane, but the resulting proteins still needed some detergent to dissolve.
They increased the replacement rate to about 50%, but the proteins were still not fully water-soluble, so they replaced all instances of glutamine, isoleucine, valine, and phenylalanine embedded in the membranes.
In this study, the researchers demonstrated their technique on four proteins that belong to a class of proteins known as G protein-coupled receptors. These proteins help cells to recognize molecules, such as hormones, or immune molecules, called chemokines, and trigger an appropriate response within the cell.
The researchers are still working towards obtaining the precise structures of these proteins using X-ray crystallography or nuclear magnetic resonance (NMR), but they performed some experiments that suggest the structures are similar. In one, they showed that the water-soluble proteins denature at nearly the same temperature as the original versions of the proteins.
Another possibility is designing water-soluble versions of the proteins that bind to molecules normally expressed by cancer cells, which could be used to diagnose tumors or identify metastatic cancer cells in blood samples.
Researchers could also create water-soluble molecules in which a membrane-bound receptor that viruses normally bind to is attached to part of an antibody. If these "decoy therapies" were injected into the body, viruses would bind to the receptors and then be cleared by the immune system, which would be activated by the antibody portion.