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PreprintCited by 0Receptor Mechanisms and SignalingProtein Structure and DynamicsProtein Kinase Regulation and GTPase Signaling

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Generic residue numbering of the GAIN domain of adhesion GPCRs

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Seufert, Florian, Pérez-Hernández, Guillermo, Pándy-Szekeres, Gáspár, Guixà-González, Ramon, Langenhan, Tobias, Gloriam, David E., Hildebrand, Peter W.·2024·Research Square
DOI 10.21203/rs.3.rs-4761600/v1

Preprint — published as 10.1038/s41467-024-55466-6 · Paper page

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Abstract

The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a concealed tethered agonist element, which is 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 six experimental and more than 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 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 folds of GAIN domains of polycystic kidney disease 1/PKD1-like proteins, which now renders positions in both GAIN domain types comparable to one another.

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Metadata

Authors
Seufert, F., Pérez-Hernández, G., Pándy-Szekeres, G., Guixà-González, R., Langenhan, T., Gloriam, D. E., & Hildebrand, P. W.
Affiliations
  • Leipzig University (DE)
  • Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
  • University of Copenhagen, HUN-REN Research Center for Natural Sciences
  • Leipzig University, Institute for Advanced Chemistry of Catalonia
  • University of Copenhagen (DK)
ORCID
Venue
Research Square
Publisher
Springer Science and Business Media LLC
Published
2024-07-19
DOI
10.21203/rs.3.rs-4761600/v1
OpenAlex
W4400830835
Cited by
0
References
2
Type
posted content
Language
en
Open access
Licence
Locations
  • Research Square (acceptedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (421152132)
  • Lundbeckfonden (R383-2022-306)
  • Novo Nordisk (NNF23OC0082561)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
GAIN domain, adhesion G protein-coupled receptors, tethered agonist, receptor activation, structural alignment, GPCRdb, domain topology, conservation hotspots

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