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Cited by 29Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesReceptor Mechanisms and Signaling

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Mechanism of receptor assembly via the pleiotropic adipokine Leptin

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Tsirigotaki, Alexandra, Dansercoer, Ann, Verschueren, Koen H. G., Marković, Iva, Pollmann, Christoph, Hafer, Maximillian, Felix, Jan, Birck, Catherine, Van Putte, Wouter, Catteeuw, Dominiek, Tavernier, Jan, Fernando Bazan, J., Piehler, Jacob, Savvides, Savvas N., Verstraete, Kenneth·2023·Nature Structural & Molecular Biology
DOI 10.1038/s41594-023-00941-9

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Abstract

The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.

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Metadata

Authors
Tsirigotaki, A., Dansercoer, A., Verschueren, K. H. G., Marković, I., Pollmann, C., Hafer, M., Felix, J., Birck, C., Van Putte, W., Catteeuw, D., Tavernier, J., Fernando Bazan, J., Piehler, J., Savvides, S. N., & Verstraete, K.
Affiliations
  • Ghent University (BE)
  • Osnabrück University (DE)
  • Centre National de la Recherche Scientifique (FR)
  • Vlaams Instituut voor Biotechnologie (BE)
Corresponding author
  • Savvides, Savvas N.
  • Verstraete, Kenneth
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2023-03-23
Volume
30
Issue
4
Pages
551-563
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-023-00941-9
OpenAlex
W4360612246
Cited by
29
References
8
Citations by year
2026: 1 · 2025: 12 · 2024: 8 · 2023: 8
FWCI
4.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
Funders
Agence Nationale de la Recherche (ANR-10-INBS-0005)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
leptin, leptin receptor, receptor assembly, trimerization, receptor activation mechanism, Ig domains
MeSH terms
Signal Transduction, Protein Isoforms, Leptin, Adipokines

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