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. 2017 Apr 24;8:86. doi: 10.3389/fendo.2017.00086

Figure 3.

Figure 3

A full-length model of the thyroid-stimulating hormone receptor (TSHR) leucine-rich repeat domain and a fragmental model of the hinge region. (A) The LRRD of the TSHR is the main binding site for hormones and autoantibodies. They interact with amino acids in the concave site of this domain, which is arranged as a beta-sheet. Hydrophobic amino acid side chains are located mainly in the inner core of the domain, thus aromatic interactions are of high importance. Although the so far solved TSHR LRRD structures are constituted by a maximum of 9 repeats (56, 57), it was suggested (53) that this domain is actually constituted by 11 repeats (r1–r11)—as also presented here in this model (designed by a chimeric model-approach, LRRD model comprises amino acids 24–288). In contrast to other known LRRD structures with similarity to the glycoprotein hormone receptor (GPHR) LRRDs (66–68), the backbone on the convex side of this domain shows only one short helical structure namely in repeat 11. The cysteines at positions 283 and 284 are known to interact with two cysteines at the C-terminal hinge region (B). Furthermore, mutations of serine 281 were identified as pathogenic (70, 71) and causing a gain of function by constitutive receptor activation. Of note, lysine 183 in repeat 7 (blue stick) was identified to be highly responsible for ligand specificity. The Lys183Arg substitution leads to a hypersensitivity for choriogonadotropin (74, 75). (B) This fragmental TSHR hinge region model (lilac-purple, amino acids 289–304 and 382–409) is adapted according to the solved follicle-stimulating hormone receptor (FSHR) ectodomain (ECD)/FSH complex structure (65) and contains several amino acids of high structural and functional importance. The cysteine 398 is located in a small beta-strand that is arranged parallel to the last beta-strand 11 of the LRRD. The two essential disulfide bridges Cys283/Cys398 and Cys284/Cys408 are shown. A third extracellular disulfide bridge between Cys301 and Cys390 stabilizes the interplay between the N- and C-terminus. Moreover, the recent FSHR ECD crystal structure bound with follitropin provided details for the first time on the second hormone-binding site of GPHRs around a conserved sulfated tyrosine (in TSHR sTyr385). This tyrosine binds into a pocket between the hormone subunits and contributes to ligand-binding properties (76).