Hsu S Y, Liang S G, Hsueh A J
Department of Gynecology and Obstetrics, Stanford University Medical School, California 94305-5317, USA.
Mol Endocrinol. 1998 Dec;12(12):1830-45. doi: 10.1210/mend.12.12.0211.
The receptors for LH, FSH, and TSH belong to the large G protein-coupled, seven-transmembrane (TM) protein family and are unique in having a large N-terminal extracellular (ecto-) domain containing leucine-rich repeats important for interaction with the glycoprotein ligands. We have identified two new leucine-rich repeat-containing, G protein-coupled receptors and named them as LGR4 and LGR5, respectively. The ectodomains of both receptors contain 17 leucine-rich repeats together with N- and C-terminal flanking cysteine-rich sequences, compared with 9 repeats found in known glycoprotein hormone receptors. The leucine-rich repeats in LGR4 and LGR5 are arrays of 24 amino acids showing similarity to repeats found in the acid labile subunit of the insulin-like growth factor (IGF)/IGF binding protein complexes as well as slit, decorin, and Toll proteins. The TM region and the junction between ectodomain and TM 1 are highly conserved in LGR4, LGR5, and seven other LGRs from sea anemone, fly, nematode, mollusk, and mammal, suggesting their common evolutionary origin. In contrast to the restricted tissue expression of gonadotropin and TSH receptors in gonads and thyroid, respectively, LGR4 is expressed in diverse tissues including ovary, testis, adrenal, placenta, thymus, spinal cord, and thyroid, whereas LGR5 is found in muscle, placenta, spinal cord, and brain. Hybridization analysis of genomic DNA indicated that LGR4 and LGR5 genes are conserved in mammals. Comparison of overall amino acid sequences indicated that LGR4 and LGR5 are closely related to each other but diverge, during evolution, from the homologous receptor found in snail and the mammalian glycoprotein hormone receptors. The identification and characterization of new members of the LGR subfamily of receptor genes not only allow future isolation of their ligands and understanding of their physiological roles but also reveal the evolutionary relationship of G protein-coupled receptors with leucine-rich repeats.
促黄体生成素（LH）、促卵泡激素（FSH）和促甲状腺激素（TSH）的受体属于大型G蛋白偶联的七跨膜（TM）蛋白家族，其独特之处在于具有一个大的N端细胞外（胞外）结构域，该结构域含有对与糖蛋白配体相互作用很重要的富含亮氨酸的重复序列。我们鉴定出了两种新的含富含亮氨酸重复序列的G蛋白偶联受体，并分别将它们命名为LGR4和LGR5。与已知糖蛋白激素受体中发现的9个重复序列相比，这两种受体的胞外结构域均含有17个富含亮氨酸的重复序列以及N端和C端侧翼富含半胱氨酸的序列。LGR4和LGR5中的富含亮氨酸重复序列是由24个氨基酸组成的阵列，与胰岛素样生长因子（IGF）/IGF结合蛋白复合物的酸性不稳定亚基以及缝隙蛋白、核心蛋白聚糖和Toll蛋白中发现的重复序列相似。在LGR4、LGR5以及来自海葵、果蝇、线虫、软体动物和哺乳动物的其他七个LGR中，跨膜区域以及胞外结构域与跨膜结构域1之间的连接高度保守，这表明它们具有共同的进化起源。与促性腺激素和TSH受体分别在性腺和甲状腺中的组织表达受限不同，LGR4在包括卵巢、睾丸、肾上腺、胎盘、胸腺、脊髓和甲状腺在内的多种组织中表达，而LGR5则存在于肌肉、胎盘、脊髓和大脑中。基因组DNA的杂交分析表明，LGR4和LGR5基因在哺乳动物中是保守的。整体氨基酸序列比较表明，LGR4和LGR5彼此密切相关，但在进化过程中与蜗牛中发现的同源受体以及哺乳动物糖蛋白激素受体有所不同。受体基因LGR亚家族新成员的鉴定和表征不仅有助于未来分离它们的配体并了解其生理作用，还揭示了含富含亮氨酸重复序列的G蛋白偶联受体的进化关系。
