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Tree-like Detergent Molecules for Membrane Proteins

Scientists at Freie Universität Berlin and University of Oxford Develop Novel Technique for the Analysis of Membrane Proteins

№ 017/2020 from Jan 29, 2020

Researchers at Freie Universität Berlin and the University of Oxford developed a method, which enables the gentle release of proteins from membranes. The German-British team, led by the chemists Prof. Dr. Kevin Pagel and Prof. Dr. Rainer Haag from the Institute of Chemistry and Biochemistry of the Freie Universität Berlin and Professor Dame Carol Robinson and Dr. Leonhard Urner from the University of Oxford, established a novel technique for the analysis of membrane proteins. The results were published in the prestigious journal Nature Communications. The study of membrane proteins is of particular importance as they are targets for nearly half of all known drugs. Until now, however, the sensitive proteins have often been destroyed during the detachment from the membrane. According to Kevin Pagel and Rainer Haag, the approach pursued at the Freie Universität Berlin will help to gain a better understanding of their function and to develop new drugs.

Proteins are vital molecular machines. More than one third of them is bound to membranes where they regulate a variety of important biological functions. Many of the drugs that are currently available on the market attach to membrane proteins in the body. “A detailed analysis of this binding is therefore of particular importance for medical research,” emphasizes Kevin Pagel. Until now, however, such an analysis has been a great challenge as the proteins are often damaged when they are released from the membrane.

Biomembranes consist of a diverse mixture of fatty acids in which a large number of different membrane proteins are embedded. Both biomembrane and membrane proteins are only poorly soluble in water. Therefore, a trick is often used for their structural investigation: “Similar to fat droplets during dish washing, membrane proteins are encapsulated in a shell of detergent molecules,” explains Leonhard Urner, who coordinated the experiments over the last four years. The weight of the proteins is then determined in a mass spectrometer – a kind of molecular balance. For this purpose, the detergent molecules need to be washed off with the help of a gas. “Unfortunately, this detergent removal also removes all natural binding partners and damages most membrane proteins. Therefore, a detailed analysis is only possible in very few cases,” he explains.

In the now published study, a large number of different tree-like detergent molecules was systematically tested for the first time. “We found compounds which help not only to retain the structure of proteins during the measurement, but also their natural binding partners. For the first time, this enabled the detailed analysis of the by far most interesting class of membrane proteins, so-called G-protein coupled receptors,” explains Rainer Haag. In the future, the technology developed here will enable scientists to investigate pharmacologically interesting membrane proteins in a much more time-efficient and cost-effective way, which in turn supports the development of new drugs.

Further Information

Publication

Urner, L. H.; Liko, I.; Yen, H.-Y.; Hoi, K.; Bolla, J. R., Gault, J.; Almeida, F. G.; Schweder, M.-P.; Shutin, D.; Ehrmann, S.; Haag, R.; Robinson, C. V.; Pagel, K.; Modular detergents tailor the purification and structural analysis of membrane proteins including G-protein coupled receptors, Nat. Commun. 2020, doi: 10.1038/s41467-020-14424-8.

Contact:

Prof. Dr. Kevin Pagel and Prof. Dr. Rainer Haag, Institute of Chemistry and Biochemistry, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Email:kevin.pagel@fu-berlin.de and haag@chemie.fu-berlin.de