A very interesting work by Sauer et al. has been recently published in Biophysical J (here) and was highlighted by a nice comment by CG Tate (see here). What the story is about? Sauer and colleagues have deployed comparative bioinformatics tools to propose single point mutations for stabilising a membrane protein, the tetracycline antiporter from Bacillus subtilis (BsTetL). Out of the 22 mutations tested, 7 were proved to increase the thermal stability of the protein: almost 32% of success! This is a very high number. Why all this interest? Following the comment by Tate, membrane proteins -that are key targets for many drugs- are difficult to be crystallised. They must be isolated from the membrane environment and solubilised before crystallised. This is achieved by using detergents that protect the hydrophobic surface of the membrane protein from the contact with water. The stability of the protein/detergent complex is considered a pre-requisite for the success of the crystallisation process. While many effort has been placed to select/design the correct detergent to envelope the membrane protein, and alternative strategy consists in making the protein more stable. But select what to mutate, because of the highly complicate procedure, is essential. In this regards, the methodology proposed by Sauer et al. could be a breakthrough. Of course, questions remain. From the long research on thermophilic proteins we know that often stability trades functionality. Ergo, making the protein more stable could lock it in not functional states. This concerns is well explained in the Tate's comment. Go there, for an elegant discussion.
