Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

The glycoprotein hormones of humans, produced in the pituitary and acting through receptors in the gonads to support reproduction and in the thyroid gland for metabolism, have co-evolved from invertebrate counterparts ^1,2 . These hormones are heterodimeric cystine-knot proteins; and their receptors bind the cognate hormone at an extracellular domain and transmit the signal of this binding through a transmembrane domain that interacts with a heterotrimeric G protein. Structures determined for the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric ^3–6 despite compelling evidence for their functioning as dimers ^7–10 . Here we describe the cryo-EM structure of the homologous receptor from a neuroendocrine pathway that promotes growth in a nematode ¹¹ . This structure is an asymmetric dimer that can be activated by the hormone from that worm ¹² , and it shares features especially like those of the thyroid stimulating hormone receptor (TSHR). When studied in the context of the human homologs, this dimer provides a structural explanation for the transactivation evident from functional complementation of binding-deficient and signaling-deficient receptors ⁷ , for the negative cooperativity in hormone action that is manifest in the 1:2 asymmetry of primary TSH:TSHR complexes ^8,9 , and for switches in G-protein usage that occur as 2:2 complexes form ^9,10 .