Generic residue numbering of the GAIN domain of adhesion GPCRs
Abstract The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a tethered agonist necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations. However, the low p...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55466-6 |
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| author | Florian Seufert Guillermo Pérez-Hernández Gáspár Pándy-Szekeres Ramon Guixà-González Tobias Langenhan David E. Gloriam Peter W. Hildebrand |
| author_facet | Florian Seufert Guillermo Pérez-Hernández Gáspár Pándy-Szekeres Ramon Guixà-González Tobias Langenhan David E. Gloriam Peter W. Hildebrand |
| author_sort | Florian Seufert |
| collection | DOAJ |
| description | Abstract The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a tethered agonist necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations. However, the low primary sequence conservation of GAIN domains has thus far hindered the knowledge transfer across different GAIN domains in human receptors as well as species orthologs. Here, we present a scheme for generic residue numbering of GAIN domains, based on structural alignments of over 14,000 modeled GAIN domain structures. This scheme is implemented in the GPCR database (GPCRdb) and elucidates the domain topology across different aGPCRs and their homologs in a large panel of species. We identify conservation hotspots and statistically cancer-enriched positions in human aGPCRs and show the transferability of positional and structural information between GAIN domain homologs. The GAIN-GRN scheme provides a robust strategy to allocate structural homologies at the primary and secondary levels also to GAIN domains of polycystic kidney disease 1/PKD1-like proteins, which now renders positions in both GAIN domain types comparable to one another. In summary, our work enables researchers to generate hypothesis and rationalize experiments related to GAIN domain function and pathology. |
| format | Article |
| id | doaj-art-8a417beb63a0404d8594000076667427 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-8a417beb63a0404d85940000766674272025-01-05T12:38:13ZengNature PortfolioNature Communications2041-17232025-01-0116111110.1038/s41467-024-55466-6Generic residue numbering of the GAIN domain of adhesion GPCRsFlorian Seufert0Guillermo Pérez-Hernández1Gáspár Pándy-Szekeres2Ramon Guixà-González3Tobias Langenhan4David E. Gloriam5Peter W. Hildebrand6Institute for Medical Physics and Biophysics, Leipzig University, Medical FacultyInstitute for Medical Physics and Biophysics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu BerlinDepartment of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2Institute for Medical Physics and Biophysics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu BerlinRudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig UniversityDepartment of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2Institute for Medical Physics and Biophysics, Leipzig University, Medical FacultyAbstract The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a tethered agonist necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations. However, the low primary sequence conservation of GAIN domains has thus far hindered the knowledge transfer across different GAIN domains in human receptors as well as species orthologs. Here, we present a scheme for generic residue numbering of GAIN domains, based on structural alignments of over 14,000 modeled GAIN domain structures. This scheme is implemented in the GPCR database (GPCRdb) and elucidates the domain topology across different aGPCRs and their homologs in a large panel of species. We identify conservation hotspots and statistically cancer-enriched positions in human aGPCRs and show the transferability of positional and structural information between GAIN domain homologs. The GAIN-GRN scheme provides a robust strategy to allocate structural homologies at the primary and secondary levels also to GAIN domains of polycystic kidney disease 1/PKD1-like proteins, which now renders positions in both GAIN domain types comparable to one another. In summary, our work enables researchers to generate hypothesis and rationalize experiments related to GAIN domain function and pathology.https://doi.org/10.1038/s41467-024-55466-6 |
| spellingShingle | 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 |
| title | Generic residue numbering of the GAIN domain of adhesion GPCRs |
| title_full | Generic residue numbering of the GAIN domain of adhesion GPCRs |
| title_fullStr | Generic residue numbering of the GAIN domain of adhesion GPCRs |
| title_full_unstemmed | Generic residue numbering of the GAIN domain of adhesion GPCRs |
| title_short | Generic residue numbering of the GAIN domain of adhesion GPCRs |
| title_sort | generic residue numbering of the gain domain of adhesion gpcrs |
| url | https://doi.org/10.1038/s41467-024-55466-6 |
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