Structural and evolutionary insights into the functioning of glycoprotein hormones and their receptors.

IF 3.2 2区 医学 Q1 ANDROLOGY Andrology Pub Date : 2025-01-27 DOI:10.1111/andr.70001
Wayne A Hendrickson, Zhen Gong
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Abstract

The neuroendocrine system that comprises the glycoprotein hormones (GpHs) and their receptors is essential for reproduction and metabolism. Each GpH hormone is an αβ heterodimer of cystine-knot proteins and its cognate receptor is a G-protein coupled receptor (GPCR) distinguished by a large leucine-rich-repeat (LRR) extracellular domain that binds the hormone and a class A GPCR transmembrane domain that signals through an associating heterotrimeric G protein. Hence, the receptors are called LRR-containing GPCRs-LGRs. The vertebrate GpHs and LGRs have co-evolved from homologs in the earliest metazoan animals, including sponges and comb jellies, but these are absent from unicellular organisms and plants. The two GpH subunits and accompanying LGR receptor of the nematode Caenorhabditis elegans are representative of the invertebrate evolutionary predecessors of human GpH proteins and their receptors, for example follicle-stimulating hormone (FSH) and the FSH receptor (FSHR). Atomic structures of the human GpHs and their receptors, which have been determined by X-ray crystallography and cryogenic electron microscopy (cryo-EM), inform the evolutionary process and provide a mechanistic understanding of the transmission of biochemical signals of hormone binding at the cell surface to the elicitation of second messengers such as cyclic AMP in the cytoplasm. There is compelling biochemical and cellular evidence for the importance of receptor dimers in GpH signaling in cells; yet, all of the human receptors are monomeric as defined beautifully by cryo-EM. Fortunately, the LGR of C. elegans is a stable dimer and its structure, when analyzed in the context of structural information from the human counterparts, predicts a hypothetical model for functionally relevant dimeric associations of the human GpH receptors.

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来源期刊
Andrology
Andrology ANDROLOGY-
CiteScore
9.10
自引率
6.70%
发文量
200
期刊介绍: Andrology is the study of the male reproductive system and other male gender related health issues. Andrology deals with basic and clinical aspects of the male reproductive system (gonads, endocrine and accessory organs) in all species, including the diagnosis and treatment of medical problems associated with sexual development, infertility, sexual dysfunction, sex hormone action and other urological problems. In medicine, Andrology as a specialty is a recent development, as it had previously been considered a subspecialty of urology or endocrinology
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