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Discovery aids membrane protein studies


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Researchers at the Salk Institute for Biological Sciences have discovered a way of making membrane proteins in bacterial cells, opening the door to new and improved treatments for a host of human diseases.

Around one-third of all the 30,000 genes in the human genome code for membrane proteins, i.e. those that integrate into the outer wall of cells and allow it to interact with the environment outside. But despite being so common, only handful have been isolated in the quality and quantity needed to study them successfully.

The problem is simple. While proteins that exist freely inside the cell can be studied relatively easily once they are cloned by inserting genes into bacteria such as Escherichia coli membrane proteins are designed to be embedded in the cell membrane to function properly. This means they need to be inserted into a cell membrane when they are created, but a good method of achieving this has eluded researchers.

Now, the Salk researchers have discovered a 'partner' molecule called Mistic that at last makes possible widespread production of membrane proteins in bacterial cell membranes. This means that they can be studied, allowing scientists to determine their atomic structure and design drugs that alter their function.

Using NMR spectroscopy Salk scientist Roland Riek led the efforts to determine Mistic's unusual structure, which consists of a bundle of four helices, like two pairs of corkscrews, that appear to automatically fold into place within the cell membrane.

"We think that these four helices give Mistic a self-integrating capability," said Riek.

"It seems that Mistic inserts autonomously into the membrane and that this facilitates the rest of the molecule, the 'cargo' protein, to undergo the folding and integration process," said Tarmo Roosild, the lead author of the study.

The auto-inserting ability of Mistic gives medical researchers a new tool that could revolutionize membrane biology. It allows them for the first time to produce large quantities of crucial membrane proteins for structural study or therapeutic research, such as ion channels and the vast family of receptors called G-protein coupled receptors (GPCRs). Approximately 1,000 GPCRs exist, involved in a wide variety of body processes from vision to sexual development as well as many endocrinological and autoimmune disorders.

The team has already successfully created dozens of such important human membrane proteins in the cell membrane of E coli using Mistic.

More than half the blockbuster drugs in the pharmaceutical industry are targeting just two classes of membrane proteins: ion channels and GPCRs.

"Figuring out how to produce them abundantly using Mistic is probably the most fascinating, pure breakthrough discovery we have ever made in my 12-year old laboratory at the Salk," said Senyon Choe, the team leader of the project.