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Receptor biology

How to control hunger

Nature Structural & Molecular Biology volume 30, pages 409–411 (2023)Cite this article

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White adipose tissue secretes the small polypeptide hormone leptin, which controls food intake and satiety. Unlike other metabolic hormones such as insulin and glucagon, leptin does not act on the major metabolic organs liver, muscle, and white adipose tissue, but instead exerts its primary function on the central nervous system.

Earlier studies demonstrate that LepR contains two distinct leptin binding sites6,7. One binding site, site 2, is located within the second cytokine-receptor homology 2 module and interacts with leptin with high affinity, while the other binding site, site 3, is located within the immunoglobulin domain and contacts leptin with lower affinity (Fig. 1a). While leptin and LepR were thought to associate in a 2:2 ratio, discerning the full structure of the dimeric complex was a challenge because of the flexible nature of extracellular domains8,9. In a paper published in Nature Communications, Saxton et al.10 report a cryo-electron microscopy (cryo-EM) structure of a stabilized leptin–LepR complex through substitution of the transmembrane domain of LepR with a dimerizing leucine zipper. The substitution greatly enhances the stability of the dimeric complex and allows the resolution of the extracellular 2:2 leptin–LepR complex. Contrary to popular belief that the two LepR monomers dimerize in a symmetric manner upon the binding of two leptin molecules, Saxton et al.10 demonstrate that the two LepR monomers associate asymmetrically and that only one leptin molecule is responsible for bridging the two monomers together (Fig. 1b). One part of the leptin molecule interacts with the high-affinity site 2 of one LepR monomer, while the other part of the same leptin molecule binds to the low-affinity site 3 of the second LepR monomer. Surprisingly, the second leptin molecule only interacts with one LepR monomer at its site 2 and faces away from the other LepR monomer. Saxton et al.10 also reveal the structure a leptin–LepR complex with truncation on the two most flexible membrane-distal regions. The truncation and the use of AlphaFold models allow notably higher resolution that is sufficient to resolve the interacting residues that constitute site 2 and site 3, confirming previous mutagenesis and structural studies. The structural model also reveals that both the LepR monomers and the leptin molecules undergo conformational changes to facilitate dimerization and stabilization of the active asymmetric conformation. This asymmetric receptor dimerization has been observed in receptor tyrosine kinases such as insulin receptor11,12 and insulin-like growth factor 1 receptor13, but not observed before in cytokine receptor complexes.

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Fig. 1: Leptin-dependent assembly and activation of LepR complex.

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Acknowledgements

E.C. is supported in part by US National Institutes of Health grants R01DK132361, R35GM142937, P30DK132710, and P30DK063608.

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  1. Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Albert Hung & Eunhee Choi

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  1. Albert Hung
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Correspondence to Eunhee Choi.

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Hung, A., Choi, E. How to control hunger. Nat Struct Mol Biol 30, 409–411 (2023). https://doi.org/10.1038/s41594-023-00963-3

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