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Cited by 5Receptor Mechanisms and SignalingProtein Structure and DynamicsBiomarkers in Disease Mechanisms

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The dimerized pentraxin-like domain of the adhesion G protein–coupled receptor 112 (ADGRG4) suggests function in sensing mechanical forces

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Kieslich, Björn, Weiße, Renato H., Brendler, Jana, Ricken, Albert, Schöneberg, Torsten, Sträter, Norbert·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105356PMC PMC10687090

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Abstract

Adhesion G protein–coupled receptors (aGPCRs) feature large extracellular regions with modular domains that often resemble protein classes of various function. The pentraxin (PTX) domain, which is predicted by sequence homology within the extracellular region of four different aGPCR members, is well known to form pentamers and other oligomers. Oligomerization of GPCRs is frequently reported and mainly driven by interactions of the seven-transmembrane region and N or C termini. While the functional importance of dimers is well-established for some class C GPCRs, relatively little is known about aGPCR multimerization. Here, we showcase the example of ADGRG4, an orphan aGPCR that possesses a PTX-like domain at its very N-terminal tip, followed by an extremely long stalk containing serine-threonine repeats. Using X-ray crystallography and biophysical methods, we determined the structure of this unusual PTX-like domain and provide experimental evidence for a homodimer equilibrium of this domain which is Ca 2+ -independent and driven by intermolecular contacts that differ vastly from the known soluble PTXs. The formation of this dimer seems to be conserved in mammalian ADGRG4 indicating functional relevance. Our data alongside of theoretical considerations lead to the hypothesis that ADGRG4 acts as an in vivo sensor for shear forces in enterochromaffin and Paneth cells of the small intestine.

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Metadata

Authors
Kieslich, B., Weiße, R. H., Brendler, J., Ricken, A., Schöneberg, T., & Sträter, N.
Affiliations
Leipzig University (DE)
Corresponding author
  • Kieslich, Björn
  • Schöneberg, Torsten
  • Sträter, Norbert
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-12
Volume
299
Issue
12
Pages
105356
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105356
PMC
PMC10687090
OpenAlex
W4387747096
Cited by
5
References
2
Citations by year
2026: 2 · 2025: 3
FWCI
0.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
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 › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
adhesion G protein-coupled receptors, homodimerization, receptor oligomerization, shear force sensing, mechanosensing, enterochromaffin cells, Paneth cells, small intestine, orphan G protein-coupled receptor, crystal structure
MeSH terms
Protein Domains, Amino Acid Sequence, Animals, Cell Adhesion, Enterochromaffin Cells, Humans, Mammals, Models, Molecular, Signal Transduction, Sequence Alignment, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray, Paneth Cells, Receptors, G-Protein-Coupled, Biophysical Phenomena, HEK293 Cells

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