Recombinant Human TSH alpha/beta Heterodimer Protein

TSH (thyroid stimulating hormone), also known as thyrotropin, is a member of the cysteine knot growth factor superfamily (1-4). It is a heterodimer of a 15 kDa unique subunit, TSH beta, with a 14 kDa alpha subunit, CGa (common glycoprotein hormone alpha) that is shared with lutropin (LH), follitropin (FSH) and chorionic gonadotropin (CG) (1-4). Beta subunits of the four glycoprotein hormones share 37-43% amino acid (aa) identity. Mature human TSH  beta shares 92%, 90%, 90%, 89%, 89%, 89%, and 88% aa identity with canine, rat, equine, mouse, bovine, porcine, and feline TSH beta, respectively. Mature human CGa shares 69%-73% aa identity with canine, rabbit, rat, mouse, bovine, ovine, porcine, feline and equine CGa. Each subunit forms a cysteine knot structure with three disulfide bridges (1). A loop of the TSH beta subunit, termed a “seat-belt”, wraps around the CGa subunit to stabilize non-covalent association of the subunits, and also confers receptor selectivity (5). Structure and charge of the three N-linked carbohydrate chains influence activity; the most complex forms have lower activity but a longer halflife (1, 5). Bovine and porcine TSH bind human TSH receptors (TSHR) with high affinity (6). The hypothalamic peptide TRH stimulates production and secretion of TSH by thyrotrophs (basophile cells) in the anterior pituitary gland (1). TSH travels to thyroid TSHR to stimulate production of thyroxine (T4) (1). In the tissues, T4 is converted to the active form of thyroid hormone, triiodothyronine (T3), which completes a feedback loop by inhibiting TSH production (1, 7). Studies in the mouse identify bone marrow as a secondary site of TSH production (8). In bone, TSH signaling through TSHR on osteoblast and osteoclast precursors negatively regulates skeletal remodeling (9, 10). Bone marrow cells that produce TSH may also circulate to the thyroid and appear to modulate thyroid hormone activity in times of immunological stress (7, 11).