A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800–900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroi...

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Veröffentlicht in:Molecular and cellular endocrinology 2007-01, Vol.260-262, p.126-136
Hauptverfasser: Puett, D., Li, Y., DeMars, G., Angelova, K., Fanelli, F.
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Li, Y.
DeMars, G.
Angelova, K.
Fanelli, F.
description The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800–900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteine-rich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR–ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG–LHR–Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH–FSHR–ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein–protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR–ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1–3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG–LHR–Gs, but considerable progress has been made in the past few years.
doi_str_mv 10.1016/j.mce.2006.05.009
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There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH–FSHR–ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein–protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR–ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1–3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. 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There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH–FSHR–ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein–protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR–ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1–3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. 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LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteine-rich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR–ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG–LHR–Gs complex, numerous interactions and conformational changes must be considered. 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subjects Amino Acid Sequence
Chorionic Gonadotropin - metabolism
G protein-coupled receptor
Gonadotropin-mediated signaling
Gs protein
GTP-Binding Proteins - metabolism
Human chorionic gonadotropin
Humans
LH receptor
Ligands
Membrane Proteins - metabolism
Molecular Sequence Data
Protein Structure, Tertiary
Receptors, LH - chemistry
Receptors, LH - metabolism
title A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein
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