Tsh Structurefunction

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TSH is a key protein controlling thyroid function through its interaction with TSH receptor in thyroid. TSH is a member of glycoprotein hormone family produced by basophiles in the anterior pituitary (Pierce and Parsons 1981; Hearn and Gomme

2000). Human TSH is a heterodimer composed of two non-covalently linked subunits, a- and TSHP-subunit. a-Subunit contains 92 amino acids and a sequence identical in all human glycoprotein hormones. TSHj3-subunit contains 118 amino acids and is unique for human TSH. The high-resolution structure of homologous to TSH human chorionic gonadotropin (hCG) has revealed that both subunits contain a central cystine-knot motif and three loops: two P-hairpin loops (L1 and L3) on one side of a cystine-knot and a long loop (L2) on the other (Lapthorn et al. 1994). The long loop in the includes two-turn The cystine-knot is made up of three central disulfide bonds, where one of the disulfide bonds threads through a ring formed by two other disulfide bonds. Similar to other glycoprotein hormones (LH, FSH and hCG), TSH hetero-dimers are stabilized by a unique segment of the p-subunit termed "seat-belt", because it wraps around the a-subunit. In light of the common a-subunit and 38% sequence identity between the hCGP- and hTSHP-subunit, homology modeling of hTSH was performed and showed expected similarities in the global conformation of these two hormones (Szkudlinski et al. 1996). Accordingly, assignment of disulfide bonds in bovine TSH P-subumt revealed bonding analogous to hCG (Fairlie et al. 1996). Thus, in three disulfide bonds

(2-52, 27-83 and 31-85) form cystine-knot motif that determines the core structure, two disulfide bonds (19-105, 88-95) are involved in "seat-belt" formation and one (17-67) links two P-hairpin loops. Such structural features result in an increased interaction between two subunits and provide stability of heterodimer in physiological conditions.

Three carbohydrate chains constitute 15-25% of TSH molecular weight. The human a-subunit contains two carbohydrate chains linked to asparagine 52 and asparagine 78, and the human contains one carbohydrate chain attached at asparagine 23. Such asparagine-linked oligosaccharides are complex-type structures displaying notable hormone-, species-, source- and production-dependent differences in their core and terminal residues. Differences in oligosaccharide structure result in physiological heterogeneity of pituitary and recombinant TSH (Szkudlinski et al. 1993). It has been very well established that co-translational attachment of site-specific oligosaccharide chains is highly important in subunit folding, dimerization, TSH dimer secretion, stability, plasma half-life and bioactivity.

As reviewed previously, TSH contains several important domains that are tightly conserved among different species or homologous hormones (Grossmann et al. 1997; Szkudlinski et al. 2002). Even minor modifications of such domains result in decreased expression, impaired receptor binding and bioactivity. These domains located within a "composite binding domain" proposed by Lapthorn et al. (Lapthorn et al. 1994) include: a-helix (a40-46), aLys51, aAsn52, the a-carboxyl terminus (a 88-92), a33-38, "the Keutmann loop" (TSHP31-52) and the "seat belt" in the P-subunit (TSHp88-105) (Szkudlinski et al. 1996; Grossmann et al. 1997) (Figure 1). In addition to the stabilizing role of the "seat-belt", recent studies involving chimeras have shown that this region is critical in conferring glycoprotein hormone specificity (Grossmann et al. 1997). Additional functionally critical residues have been identified

Figure 1. The schematic drawing ofhTSH structure. For clarity the carbohydrate chains are not shown. The a-subunit backbone is shown as a gray line, the (i-subunit chain as a black line. Important domains are marked directly within the line drawings. The peripheral (5-hairpin loops are marked: aL\, aL3 in the a-subunit and BL1 , BL3 in the B-subunit. Two long loops are aL2 with a-helical structure and BL2 or the "Keutmann loop."

Figure 1. The schematic drawing ofhTSH structure. For clarity the carbohydrate chains are not shown. The a-subunit backbone is shown as a gray line, the (i-subunit chain as a black line. Important domains are marked directly within the line drawings. The peripheral (5-hairpin loops are marked: aL\, aL3 in the a-subunit and BL1 , BL3 in the B-subunit. Two long loops are aL2 with a-helical structure and BL2 or the "Keutmann loop."

by studies of patients with mutations in TSH(3 subunit gene [see (Szkudlinski, et al. 2002)].

Several other domains involved in the modulation of TSH and gonadotropin function have been described in the last decade. Studies employing combination of alanine with proline scanning mutagenesis have revealed the importance of con formation (a40-46) in TSH bioactivity (Szkudlinski et al. 1996). Further, the 11-20 region in the a-subunit with a cluster ofbasic residues [(K-K/R-K—K/R); lysine(K), arginine (R)] present in all vertebrates except hominoids (apes and humans) has been recognized as an important motif in the evolution of TSH and gonadotropin bioactivity in primates (Szkudlinski et al. 1996; Szkudlinski et al. 2002). Selective elimination of basic residues in this domain of a-subunit resulted in a major decrease of receptor binding affinity and bioactivity of TSH in higher primates. Conversely, reconstitution of such basic motif resulted in a major increase in bioactivity of human TSH. It provided the first evidence that introduction of basic residues in selected sites in peripheral loops may permit design of a new class of TSH analogs (see below).

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