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Publication Abstract from PubMed

A family of leucine-rich-repeat-containing G-protein-coupled receptors (LGRs) mediate diverse physiological responses when complexed with their cognate ligands. LGRs are present in all metazoan animals. In humans, the LGR ligands include glycoprotein hormones (GPHs) chorionic gonadotropin (hCG), luteinizing hormone, follicle-stimulating hormone (hFSH), and thyroid-stimulating hormone (hTSH). These hormones are alphabeta heterodimers of cystine-knot protein chains. LGRs and their ligand chains have coevolved. Ancestral hormone homologs, present in both bilaterian animals and chordates, are identified as alpha2beta5. We have used single-wavelength anomalous diffraction and molecular replacement to determine structures of the alpha2beta5 hormone from Caenorhabditis elegans (Cealpha2beta5). Cealpha2beta5 is unglycosylated, as are many other alpha2beta5 hormones. Both Hsalpha2beta5, the human homolog of Cealpha2beta5, and hTSH activate the same receptor (hTSHR). Despite having little sequence similarity to vertebrate GPHs, apart from the cysteine patterns from core disulfide bridges, Cealpha2beta5 is generally similar in structure to these counterparts; however, its alpha2 and beta5 subunits are more symmetric as compared with alpha and beta of hCG and hFSH. This quasisymmetry suggests a hypothetical homodimeric antecedent of the alpha2beta5 and alphabeta heterodimers. Known structures together with AlphaFold models from the sequences for other LGR ligands provide representatives for the molecular evolution of LGR ligands from early metazoans through the present-day GPHs. The experimental Cealpha2beta5 structure validates its AlphaFold model, and thus also that for Hsalpha2beta5; and interfacial characteristics in a model for the Hsalpha2beta5:hTSHR complex are similar to those found in an experimental hTSH:hTSHR structure.

Crystal structure of LGR ligand alpha2/beta5 from Caenorhabditis elegans with implications for the evolution of glycoprotein hormones.,Gong Z, Wang W, El Omari K, Lebedev AA, Clarke OB, Hendrickson WA Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2218630120. doi: , 10.1073/pnas.2218630120. Epub 2022 Dec 27. PMID:36574673^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.