Adhesion GPCRs are a category of sensors located on cell surfaces that play a role in various bodily functions and diseases. Unfortunately, our understanding of them is still limited, hindering their use in therapies. Now, researchers at the Collaborative Research Centre (CRC) 1423 at Leipzig University have created a new numbering system specifically for the GAIN domain, a protein domain found in all adhesion GPCRs. This system aims to enhance our understanding of how this protein domain influences disease and to facilitate more precise experimental methodologies. The findings are published in the journal Nature Communications.
Adhesion G protein-coupled receptors encompass a large group of membrane proteins that respond to chemical and mechanical signals in the body. The GAIN domain is crucial for activating these adhesion GPCRs. However, prior research faced challenges due to the significant differences in the amino acid sequences of various GAIN domains, which hindered the ability to share knowledge and conduct comparative analyses. The newly created numbering system from Leipzig University standardizes the framework for accurately transferring research findings among different model systems and human studies. This system was developed through the examination of over 14,000 modeled structures within the GAIN domain, utilizing state-of-the-art AI methods.
Peter Hildebrand, a Professor of Membrane and Cell Biophysics at Leipzig University and the leader of the international study, stated, “Our new numbering system represents a significant advancement in GPCR research. It will promote basic research and spur comparative investigations. It lays a strong groundwork for further explorations in biochemistry, bioinformatics, and structural biology.” For instance, this new system allows for a clearer understanding of mutations in GAIN domains that are relevant to diseases, including cancer.
Insights into Kidney Disease
The researchers found that their numbering system can also be used to examine and compare the GAIN domains present in proteins associated with polycystic kidney disease, a genetic disorder that leads to the development of fluid-filled cysts in the kidneys and other organs.
Florian Seufert, the first author of the study and a doctoral researcher at the Institute of Medical Physics and Biophysics, noted, “The multidisciplinary collaboration at CRC 1423, along with our connections in Berlin and Copenhagen, contributed diverse viewpoints to our project. This collaboration has allowed us to create a user-friendly system, which opens up numerous new research avenues. We are already employing this system to further investigate the function of the GAIN domain in two ongoing projects.”
The new numbering system has been incorporated into the widely recognized international GPCR database, ensuring global access and knowledge sharing among researchers worldwide.
