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Researchers uncover how transporter proteins break cell membrane barriers

A study funded in part by the EU has shed new light on the structure and functioning of transporter proteins, the catalysts that help substances cross cell membranes. An international team of researchers has clarified how transporter proteins get chemical compounds across the ...

A study funded in part by the EU has shed new light on the structure and functioning of transporter proteins, the catalysts that help substances cross cell membranes. An international team of researchers has clarified how transporter proteins get chemical compounds across the cell membrane and, importantly, how they block other substances from getting through. The study was funded under the Sixth Framework Programme (FP6), and was published online in the journal Science Express on 16 October. Professor So Iwata of Imperial College London, UK, said the research uncovers the detailed molecular function of a significant membrane protein. 'We now know how the protein facilitates the movement of hydantoin across the cell membrane without letting any other substances through at the same time,' he explained. 'A number of cell membrane transport proteins will probably share this mechanism, even those in the human body [...]. This is an important step forward in our understanding of the fundamental processes which occur in cells.' Professor Peter Henderson of the University of Leeds, co-author of the study, opined that this latest development will 'help chemists and industrial sponsors to design and develop drugs to manipulate their activities and treat patients'. 'The major problem was to produce enough protein in the structural studies,' Professor Henderson said. Methods to maximise the expression of transporter proteins in bacteria and purify them, he explained, had been developed by the collaboration. 'This will help the proteins retain their biological activity,' he said. 'We could then maintain a "pipeline" to supply them to experts in a technique called "protein crystallography", which requires very-high-intensity X-rays,' he added. Such X-rays are available at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France and the Diamond Light Source national synchrotron facility in Oxfordshire, UK. Researchers from the Department of Life Sciences at Imperial College London visualised the transporter protein Microbacterium hydantoin permease (Mhp1) transporting molecules of hydantoin across its otherwise resistant cell membrane, the report said. Mhp1 is located in the oily membrane surrounding bacterial cells, and the successful entry of Mhp1 results in the conversion of molecules into useful amino acids, according to the report. Because amino acids are used in the development of food and drink supplements, they are hugely important to business and to the pharmaceutical industry in particular. The researchers evaluated the Mhp1 protein's structure pre- and post-entry of the hydantoin molecule. They demonstrated that Mhp1 exposes its outer-facing side, giving hydantoin the opening it needs to penetrate the barrier. The pathway then closes behind the bound molecule, banning any other substances from entering. Hydantoin is released into the cell once the inward-facing side opens, the researchers said. The report highlights that membrane transporters can be classified into three major groups: the primary group, which consists of active transporters that use energy released from light, redox reactions or ATP hydrolysis to transport substances; the secondary group, which comprises active transporters that use free energy stored in an ion gradient; and a third group, which conducts facilitated diffusion without energy input. The researchers began their exploration of this protein eight years ago in cooperation with the Japanese company Ajinomoto Inc. Dr Shinichi Suzuki initially discovered the function of the Mhp1 protein at Leeds University and the work has been patented in Japan and the US. The study was supported in part by the European Membrane Protein consortium (E-MeP), a research platform that focuses on developing and implementing new technologies that contribute to understanding membrane-protein-related human diseases.