Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, 94720, USA.
Nat Commun. 2023 Mar 31;14(1):1797. doi: 10.1038/s41467-023-37169-6.
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.
瘦素是一种脂肪细胞衍生的蛋白激素，通过在部分下丘脑神经元中激活瘦素受体（LepR）-STAT3 信号轴来促进饱腹感和能量稳态。然而，在肥胖症中，瘦素信号被失调，尽管循环瘦素水平很高，但食欲仍然升高。为了深入了解瘦素受体激活的机制，我们使用单颗粒 cryo-EM 确定了稳定的瘦素结合 LepR 信号复合物的结构。该结构揭示了一种不对称的结构，其中单个瘦素通过两个不同的受体结合位点诱导 LepR 二聚化。对瘦素-LepR 结合界面的分析揭示了与人类肥胖相关突变的分子基础。基于结构设计的使不对称 LepR 二聚体失稳的瘦素变体产生部分激动剂和偏倚激动剂，它们在存在野生型瘦素的情况下部分抑制 STAT3 的激活，并使 STAT3 的激活与 LepR 负调节剂分离。总之，这些结果揭示了 LepR 激活的结构基础，并为 LepR 下游信号通路的差异可塑性提供了深入了解。
