Editorial: TSH Receptor and Autoimmunity

摘要

Introduction Over time it has become clear that the fascination with the TSH receptor (TSHR) is not only its complexity and its relationship to human disease but the fact that it keeps teaching us fundamental biology at all levels; cellular, molecular, and genetic. There are good examples of each of these facets in this cutting edge collection of papers. This contribution provides a brief and broad overview highlighting those areas of active progress by briefly eluding to some of the contributions in this collection. The TSHR is a member of the class A family of G-protein coupled receptors (GPCR) with seven transmembrane helices traversing the plasma membrane and a large extracellular ectodomain. The ectodomain (ECD) is linked to a distal signal-specific domain—the hinge region—which is attached to a transmembrane domain (TMD) consisting of extracellular (ECL) and intracellular (ICL) loops ( Figure 1 ). A partial TSHR ectodomain (residues 1–260) has been crystallized either bound to a stimulating TSHR antibody and/or a blocking TSHR antibody ( 1 , 5 ) and recently in an unbound native state with stabilizing mutations. Like other GPCRs, the TSH receptor can also not exist in an ensemble of conformational states which can lead to its varied signaling potential. The review by Kleinau et al. in this collection takes a comprehensive look at the structure-function relationship of the TSHR via modeling and mutational approaches. It is now well-known that the full-length TSHR undergoes complex post translational processing ( 6 , 7 ) inclusive of common protein modifications such as glycosylation and phosphorylation and even whole receptor modifications such as cleavage and multimerization ( 7 , 8 ) thus resulting in a surprising variety of receptor configurations, many of which are expressed on the cell surface ( 9 ) and in some cases even shed from the cell surface ( 10 ). Although the shed receptor forms have not been conclusively demonstrated in the serum of patients with Graves' disease (GD), probably secondary to degradation, the evidence that these and other receptor structures are critical to the immunopathogenesis of GD has been well-covered in the review by Inaba et al. Figure 1 Homology model of the entire TSH holoreceptor. This model highlights the tripartite structure of the TSHR. The ectodomain, shown in gray/black, is made up of 10 leucine-rich repeat domains (LRD) characterized as a “scythe-blade” shaped structure with loops and β pleated sheets obtained from the published crystal structure ( 1 ) (PDB:3G04). The region connecting the LRD and transmembrane domain (TMD), known as the “hinge” region, has recently been crystallized for the FSH receptor ( 2 ) (PDB:4AY9) and is shown as a looped structure (orange) with a helix conformation close to the carboxyl end of the LRD. The hinge in the TSHR has an additional sequence insert and is larger than in the FSH receptor. Therefore, amino acids 305-381 are missing in the illustrated model ( 3 ) and this insert is depicted as a closed dotted loop. The TMD (yellow), with its seven helices, is depicted as cylindrical structures connected to each other by the specific TSHR intra and extracellular loops. The TMD is the region that harbors the allosteric binding pockets for the SMLs. LRD, leucine-rich domain; TMD, transmembrane domain; ECL, extracellular loops; and ICL, intracellular loops [Figure adapted from ( 4 )]. Signal transduction at the TSHR is complex because of the promiscuous nature of the TSHR in engaging with different G proteins ( 11 ). In addition, the TSHR signals can be both G protein dependent and G protein independent. The TSHR has been shown to engage predominantly β-arrestin-2 for internalization ( 12 ) and arrestin-1, in human osteoblast cells, for differentiation, and MAP kinase signaling ( 13 ). In addition, it has long been known that the TSHR is involved with the IGF1/insulin receptor in thyroid cells and the “marriage” of these two receptors in fibroblasts has suggested their involvement in Graves' eye disease pathophysiology as well-reviewed by Smith et al. . The complex life cycle of GPCRs such as the TSHR ( Figure 2 ) has also begun to be revealed showing that these types of GPCRs, after being sequestered via clathrin-coated pits or caveolin scaffolding proteins, are still able to signal after internalization. New evidence points out that these internalized receptors can lead to a “second wave” of signals from the TSHR ( 14 ). The result is that not only does the receptor come in multiple configurations but there are also multiple signal pathways that may or may not be initiated as the receptor conformation changes on ligand binding and this may continue after the receptors are internalized. The days of thinking simply of the TSH induced cyclic AMP response coming only from the surface receptors have long gone. Single-particle electron microscopy has confirmed the presence of intracellular megaplexes which consist of a GPCR bound to