STRUCTURE AND CELLULAR BIOLOGY OF GPH RECEPTORS

GPH 受体的结构和细胞生物学

• 批准号: 6131934
• 负责人: JAMES Alan DIAS
• 金额: $ 27.68万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6131934
• 关键词: conformation; follicle stimulating hormone; glycosylation; gonadotropins; granulosa cell; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; human tissue; laboratory rabbit; mitogen activated protein kinase; nuclear magnetic resonance spectroscopy; posttranslational modifications; protein structure function; receptor binding; receptor expression; site directed mutagenesis; tissue /cell culture; yeast two hybrid system

DESCRIPTION: (Adapted from the applicant's abstract) The pituitary/placental glycoprotein hormone receptor (GPHR) family includes follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor, thyroid stimulating hormone receptor and chorionic gonadotropin receptor. Glycoprotein hormones control reproduction, sexual development and thyroid function. The overall goal of this research is to better understand FSHR structure, signaling and turnover. The field currently has no molecular structure for the GPHR. To understand the structure, significance, and mechanisms of GPHR regulation a tractable approach is to determine the structure of smaller biologically active domains of the GPHR. This laboratory has discovered a biologically active, receptor domain, which could provide the first structural test of the current receptor molecular models. The structure of this autologously-acting hFSHR peptide domain will be determined by NMR spectroscopy. This structure determination and mutagenesis of native receptor at this locus, will be used to guide synthesis of conformationally stable forms of the peptide to develop more potent antagonists of FSH action. The field has only recently substantiated a model that cytoplasmic mitogen activated protein kinase signaling pathways are activated by FSH. The complexity of these pathways, and their relationships to mechanisms through protein-protein interactions wit the receptor cytoplasmic domains. This laboratory has identified candidate genes, which are interacting partners with hFSHR, detected u sing a partial yeast genetic screen of mature human ovary mRNA. Since these proteins may coordinate the cell biology of FSHR signaling and trafficking they will be studied to determine their validity as interacting partners, and potential regulators of FSHR signal transduction. A full library screen will be executed enabling detection of rare messages. The field, currently accepts a one hormone-one receptor model of activation. Determination of the three dimensional structure of fully glycosylated fully active human FSH during the current grant period, revealed the hFSH belongs to the cystine knot growth factor family as does hCG. Based upon other members of this cystine knot growth factor family which activate cellular responses by inducing dimerization of their single pass membrane cognate receptors, an alternative model of activation can be proposed and is underpinned by recent studies showing dimerization of seven pass GPCRs. A goal then, is to elucidate the oligomerization state of human FSHR and how it relates to hFSHR activation and attenuation of hormonal response.

描述：（改编自申请人的摘要）垂体/胎盘 糖蛋白激素受体（GPHR）家族包括刺激的卵泡 激素受体（FSHR），黄体生成激素受体，甲状腺刺激 激素受体和绒毛膜促性腺激素受体。糖蛋白激素 控制繁殖，性发育和甲状腺功能。总体目标 这项研究是更好地了解FSHR结构，信号传导和 周转。该领域目前没有GPHR的分子结构。到 了解GPHR调节A的结构，意义和机制 可处理的方法是确定较小的生物活性的结构 GPHR的域。该实验室发现了一个具有生物活性的， 受体结构域，可以提供电流的第一个结构测试 受体分子模型。这种自体作用的HFSHR的结构 肽结构域将通过NMR光谱法确定。这个结构 在该基因座的天然受体的测定和诱变将用于 指导构象稳定形式的肽的合成以发展更多 FSH动作的有效拮抗剂。该领域直到最近才证实 模型表明细胞质有丝分裂激活的蛋白激酶信号通路是 被FSH激活。这些途径的复杂性及其与 通过蛋白质 - 蛋白质相互作用的机制，使受体细胞质具有 域。该实验室已经确定了正在相互作用的候选基因 与HFSHR合作伙伴，检测到您唱了一个成熟的部分酵母遗传筛选 人卵巢mRNA。由于这些蛋白质可以协调FSHR的细胞生物学 信号传导和贩运​​他们将被研究以确定其有效性 相互作用的伙伴和FSHR信号转导的潜在调节剂。一个 完整的库屏幕将被执行，以允许检测稀有消息。这 场，目前接受一种激活的一种激素模型。 完全糖基化的三维结构的确定 在当前赠款期间，主动人工FSH揭示了HFSH属于 Cystine结生长因子家族和HCG一样。基于其他成员 这个胱氨酸结生长因子家族，通过 诱导其单个通过膜同源受体的二聚化，一个 可以提出替代激活模型，并由最近的基础 研究表明七个通过GPCR的二聚化。然后，目标是阐明 人FSHR的寡聚状态及其与HFSHR激活的关系 和激素反应的衰减。