Vertebrate glycoprotein hormone heterodimers are stabilized by a strand of their ␤-subunits known as the "seatbelt" that is wrapped around loop 2 of their ␣-subunits (␣2). The cysteine that terminates the seatbelt is "latched" by a disulfide to a cysteine in ␤-subunit loop 1 (␤1) of all vertebrate hormones except some teleost follitropins (teFSH), wherein it is latched to a cysteine in the ␤-subunit NH 2 terminus. As reported here, teFSH analogs of human choriogonadotropin (hCG) are assembled

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... a pathway in which the subunits dock before the seatbelt is latched; assembly is completed by wrapping the seatbelt around loop ␣2 and latching it to the NH 2 terminus. This differs from hCG assembly, which occurs by threading the glycosylated end of loop ␣2 beneath the latched seatbelt through a hole in the ␤-subunit. The seatbelt is the part of the ␤-subunit that has the greatest influence on biological function. Changes in its sequence during the divergence of lutropins, follitropins, and thyrotropins and the speciation of teleost fish may have impeded heterodimer assembly by a threading mechanism, as observed when the hCG seatbelt was replaced with its salmon FSH counterpart. Whereas wrapping is less efficient than threading, it may have facilitated natural experimentation with the composition of the seatbelt during the co-evolution of glycoprotein hormones and their receptors. Migration of the seatbelt latch site to the NH 2 -terminal end of the ␤-subunit would have facilitated teFSH assembly by a wraparound mechanism and may have contributed also to its ability to distinguish lutropin and follitropin receptors. . 1 The abbreviations used are: FSH, follitropin; hCG, human choriogo-nadotropin; hFSH, human follitropin; hTSH, human thyrotropin; ␣2, ␣-subunit loop 2; ␤1, ␤2, ␤3, ␤-subunit loops 1, 2, and 3, respectively; s/hCG␤, chimera of chum salmon FSH and hCG ␤-subunits; NH 2 terminus, amino-terminal end of the chum salmon ␤-subunit; SB, chum salmon seatbelt; TL, chum salmon seatbelt tensor loop; St, chum salmon seatbelt strap; tsFSH, teleost follitropin; LH, lutropin. The structures of the analogs used in this work can be determined by reference to Fig. 2 .