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PreprintCited by 2Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and Interactions

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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, Bazan, J. Fernando, Piehler, Jacob, Savvides, Savvas N., Verstraete, Kenneth·2022·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2022.12.01.518327

Preprint — published as 10.1038/s41594-023-00941-9 · Paper page

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Abstract

The adipokine Leptin activates its type I cytokine 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. Here, we show that Leptin:LEP-R assemblies adopt an unprecedented structure within the type I cytokine receptor family featuring 3:3 stoichiometry. We validate Leptin-induced trimerization of LEP-R in the plasma membrane of living cells via multicolor single molecule microscopy. In mediating such assemblies Leptin undergoes drastic restructuring that activates its site III for binding to the Ig-domain of an adjacent LEP-R molecule in the complex. These interactions are abolished by pathological mutations linked to obesity. Collectively, our study uncovers an evolutionarily conserved Leptin:LEP-R assembly as a new mechanistic blueprint for Leptin-mediated signaling in physiology and disease, including insights into how the lowly abundant signaling-competent isoforms of LEP-R can productively participate in 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., Bazan, J. F., Piehler, J., Savvides, S. N., & Verstraete, K.
Affiliations
  • Ghent University (BE)
  • Osnabrück University (DE)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Savvides, Savvas N.
  • Verstraete, Kenneth
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2022-12-01
DOI
10.1101/2022.12.01.518327
OpenAlex
W4311193954
Cited by
2
References
3
Citations by year
2024: 1 · 2023: 1
Type
posted content
Language
en
Open access
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion)
Funders
  • Diamond Light Source
  • Agence Nationale de la Recherche (ANR-10, ANR-10-INBS-0005)
  • Universiteit Gent
  • French Infrastructure for Integrated Structural Biology (ANR-10-INBS-0005)
  • Vlaamse regering
  • Deutsches Elektronen-Synchrotron
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 › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords
leptin, leptin receptor, receptor assembly, receptor oligomerization, Ig domains, single-molecule microscopy, leptin signaling, hypothalamus

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