Zabeau Lennart, Defeau Delphine, Van der Heyden José, Iserentant Hannes, Vandekerckhove Joel, Tavernier Jan
Flanders Interuniversity Institute for Biotechnology, VIB09, Department of Medical Protein Research, Ghent University, Faculty of Medicine and Health Sciences, Baertsoenkaai 3, B-9000 Ghent, Belgium.
Mol Endocrinol. 2004 Jan;18(1):150-61. doi: 10.1210/me.2003-0078. Epub 2003 Oct 2.
The leptin receptor (LR), a member of the class I cytokine receptor family, is composed of a single subunit. Its extracellular domain consists of two so-called cytokine receptor homology domains, separated by an Ig-like domain, and two additional fibronectin type III modules. Requirements for LR activation were examined using a complementation strategy. Two LR mutants, LR-FFY-Deltabox 1 and LR-F3, deficient in Janus kinase or signal transducer and activator of transcription (STAT) activation, respectively, were only able to generate a STAT3-dependent signal when coexpressed. Based on the requirements for Janus kinase/STAT signaling, and on the lack of complementation with similar receptor constructs, but containing the extracellular domain of the homodimeric erythropoietin receptor, this observation can be explained only by higher order LR clustering. Using a panel of deletion mutants we were able to define a role for the cytokine receptor homology 1 and Ig-like domains in leptin signaling. Moreover, we demonstrate a nonredundant function for the individual receptor chains within the homomeric LR complex. Based on these data, we propose a possible model for LR clustering.
瘦素受体（LR）是I类细胞因子受体家族的成员，由单个亚基组成。其胞外结构域由两个所谓的细胞因子受体同源结构域组成，中间隔着一个Ig样结构域，还有另外两个纤连蛋白III型模块。使用互补策略研究了LR激活的条件。两个LR突变体，分别为缺乏Janus激酶或信号转导子和转录激活子（STAT）激活的LR-FFY-Deltabox 1和LR-F3，只有在共表达时才能产生依赖于STAT3的信号。基于对Janus激酶/STAT信号传导的要求，以及与类似受体构建体（但含有同二聚体促红细胞生成素受体的胞外结构域）缺乏互补性，这一观察结果只能通过高阶LR聚集来解释。使用一组缺失突变体，我们能够确定细胞因子受体同源结构域1和Ig样结构域在瘦素信号传导中的作用。此外，我们证明了同聚体LR复合物中各个受体链具有非冗余功能。基于这些数据，我们提出了一个LR聚集的可能模型。
