Núñez Miguel Ricardo, Sanders Jane, Furmaniak Jadwiga, Smith Bernard Rees
FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU, UK.
Auto Immun Highlights. 2017 Dec;8(1):2. doi: 10.1007/s13317-016-0090-1. Epub 2016 Dec 5.
The thyroid-stimulating hormone receptor (TSHR) is the target autoantigen for TSHR-stimulating autoantibodies in Graves' disease. The TSHR is composed of: a leucine-rich repeat domain (LRD), a hinge region or cleavage domain (CD) and a transmembrane domain (TMD). The binding arrangements between the TSHR LRD and the thyroid-stimulating autoantibody M22 or TSH have become available from the crystal structure of the TSHR LRD-M22 complex and a comparative model of the TSHR LRD in complex with TSH, respectively. However, the mechanism by which the TMD of the TSHR and the other glycoprotein hormone receptors (GPHRs) becomes activated is unknown.
We have generated comparative models of the structures of the inactive (TMD_In) and active (TMD_Ac) conformations of the TSHR, follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) TMDs. The structures of TMD_Ac and TMD_In were obtained using class A GPCR crystal structures for which fully active and inactive conformations were available.
Most conserved motifs observed in GPCR TMDs are also observed in the amino acid sequences of GPHR TMDs. Furthermore, most GPCR TMD conserved helix distortions are observed in our models of the structures of GPHR TMDs. Analysis of these structures has allowed us to propose a mechanism for activation of GPHR TMDs.
Insight into the mechanism of activation of the TSHR by both TSH and TSHR autoantibodies is likely to be useful in the development of new treatments for Graves' disease.
促甲状腺激素受体（TSHR）是格雷夫斯病中促甲状腺激素受体刺激性自身抗体的靶自身抗原。TSHR由富含亮氨酸的重复结构域（LRD）、铰链区或裂解结构域（CD）和跨膜结构域（TMD）组成。TSHR LRD与促甲状腺刺激性自身抗体M22或促甲状腺激素（TSH）之间的结合方式已分别从TSHR LRD-M22复合物的晶体结构和TSHR LRD与TSH复合物的比较模型中获得。然而，TSHR的TMD以及其他糖蛋白激素受体（GPHRs）被激活的机制尚不清楚。
我们生成了TSHR、促卵泡激素受体（FSHR）和促黄体生成素受体（LHR）TMD的非活性（TMD_In）和活性（TMD_Ac）构象的结构比较模型。TMD_Ac和TMD_In的结构是使用具有完全活性和非活性构象的A类GPCR晶体结构获得的。
在GPCR TMD中观察到的大多数保守基序在GPHR TMD的氨基酸序列中也有观察到。此外，在我们的GPHR TMD结构模型中观察到了大多数GPCR TMD保守螺旋扭曲。对这些结构的分析使我们能够提出一种GPHR TMD激活机制。
深入了解TSH和TSHR自身抗体激活TSHR的机制可能有助于开发格雷夫斯病的新治疗方法。
