New numbering system facilitates comparability of protein domains

Researchers analyse models using AI

30-Jan-2025

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Adhesion GPCRs are a group of cell-surface sensors associated with many body functions and diseases. However, they are not yet sufficiently understood to be exploited for therapies. Collaborative Research Centre (CRC) 1423 at Leipzig University aims to change this. Scientists at the Faculty of Medicine have now developed an innovative numbering system for the GAIN domain, a protein domain common to all adhesion GPCRs. It should help to better understand the role of this protein domain in disease and pave the way for more precise experimental approaches. The research has been published in the journal Nature Communications.

Adhesion G protein-coupled receptors are a large class of membrane proteins that detect chemical and mechanical stimuli in the body. The GAIN domain plays a central role in the activation of adhesion GPCRs. Until now, research has been limited by the low similarity of the amino acid sequences of different GAIN domains, which has hampered knowledge transfer and comparative analysis. The new numbering system, developed by researchers at Leipzig University, provides a standardised basis for the accurate transfer of research results between different model systems and humans. It is based on the analysis of over 14,000 modelled structures in the GAIN domain, generated using the latest AI techniques.

Peter Hildebrand, Professor of Membrane and Cell Biophysics at Leipzig University, who led the international study, says: “Our new numbering system is an important step forward in GPCR research. It will facilitate basic research and encourage comparative studies. It provides a solid foundation for further research in biochemistry, bioinformatics and structural biology.” For example, the newly developed system enables a better understanding of disease-relevant mutations in GAIN domains, providing a deeper insight into their role in diseases such as cancer.

Analysis useful for kidney disease

In the new study, the scientists found that their numbering system also made it possible to analyse and compare the GAIN domains of polycystic kidney disease proteins. This genetic disease causes fluid-filled cysts to form in the kidneys and other organs.

Florian Seufert, first author of the paper and a doctoral researcher at the Institute of Medical Physics and Biophysics, says: “The interdisciplinary work in CRC 1423 and our contacts in Berlin and Copenhagen bring a variety of perspectives to such a project. This has allowed us to develop our system in a user-friendly way, opening the door to many new research opportunities. We are already using the system to support two projects in which we are further investigating the function of the GAIN domain.”

The new numbering system has been integrated into the widely used international database on GPCRs, facilitating global access and knowledge sharing for researchers.

Original publication

Florian Seufert, Guillermo Pérez-Hernández, Gáspár Pándy-Szekeres, Ramon Guixà-González, Tobias Langenhan, David E. Gloriam, Peter W. Hildebrand; "Generic residue numbering of the GAIN domain of adhesion GPCRs"; Nature Communications, Volume 16, 2025-1-2

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