Structural insights into the mechanism of leptin receptor activation

Robert A. Saxton (), Nathanael A. Caveney, Maria Dolores Moya-Garzon, Karsten D. Householder, Grayson E. Rodriguez, Kylie A. Burdsall, Jonathan Z. Long and K. Christopher Garcia ()
Additional contact information
Robert A. Saxton: Stanford University School of Medicine
Nathanael A. Caveney: Stanford University School of Medicine
Maria Dolores Moya-Garzon: Stanford University School of Medicine, Sarafan ChEM-H, Stanford University
Karsten D. Householder: Stanford University School of Medicine
Grayson E. Rodriguez: Stanford University School of Medicine
Kylie A. Burdsall: Stanford University School of Medicine
Jonathan Z. Long: Stanford University School of Medicine, Sarafan ChEM-H, Stanford University
K. Christopher Garcia: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)–STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin–LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37169-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37169-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37169-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().