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PreprintCited by 3Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeuropeptides and Animal Physiology

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Osteocalcin binds to a GPRC6A Venus fly trap allosteric site to positively modulate GPRC6A signaling

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Agarwal, Rupesh, Pi, Min, Ye, Ruisong, Smith, Micholas Dean, Smith, Jeremy C., Quarles, L. Darryl·2022·FASEB BioAdvances
DOI 10.1101/2022.02.15.480526PMC PMC11467737

Preprint — published as 10.1096/fba.2024-00025 · Paper page

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Abstract

GPRC6A is a member of the Family C G-protein coupled receptors that is activated by cations, L-amino acids, the osteocalcin (Ocn) peptide, and testosterone. GPRC6A functions as a master regulator of energy metabolism and sex hormone production. Based on homology to the related receptors mGluR5 and CaSR, GPRC6A’s multiple ligand specificity is likely based on an orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain together with two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7TM domain. Here, we show that Ocn acts as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L-amino acids. In agreement with this finding, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations provide a structural framework for understanding the ability of multiple distinct classes of compounds to activate GPRC6A and set the stage to develop novel small molecules to activate and inhibit this receptor.

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Metadata

Authors
Agarwal, R., Pi, M., Ye, R., Smith, M. D., Smith, J. C., & Quarles, L. D.
Affiliations
  • Oak Ridge National Laboratory (US)
  • University of Tennessee Health Science Center (US)
Corresponding author
  • Pi, Min
  • Smith, Jeremy C.
  • Quarles, L. Darryl
ORCID
Venue
FASEB BioAdvances
Publisher
openRxiv
Published
2022-02-15
Volume
6
Issue
9
Pages
365-376
ISSN
2573-9832 (ISSN-L)
DOI
10.1101/2022.02.15.480526
PMC
PMC11467737
OpenAlex
W4401591301
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 1 · 2024: 1
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • FASEB BioAdvances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120567, R01DK121132)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR071930)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
GPRC6A, osteocalcin, positive allosteric modulators, G protein-coupled receptor signaling, ligand binding sites, orthosteric binding site, alternative splicing, receptor activation, energy metabolism

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