Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone–receptor interactions

Jiang, Xuliang; Dréano, Michel; Buckler, David R.; Cheng, Shirley V.; Ythier, Arnaud; Wu, Hao; Hendrickson, Wayne A.; Tayar, Nabil El

doi:10.1016/s0969-2126(01)00272-6

Cited by 180 publications

(109 citation statements)

References 78 publications

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“…R genes are unlikely to have as regular a structure as PRI because the amino acids in the backbone are more variable and there is less evidence that they form regular ␣-helices (Hammond-Kossack and Jones 1997; Jones and Jones 1997). Three-dimensional modeling suggests that the thyrotropin-and choriogonadotropin-receptor domains and LRRs of other proteins have less regular LRR structures but still comprise arrays of ␤-strand/␤-turn structures (Kajava et al 1995;Jiang et al 1995;Kajava 1998).…”

Section: Clusters Of Resistance Genes Genome Research 1115mentioning

confidence: 99%

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

1998

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Classical genetic and molecular data show that genes determining disease resistance in plants are frequently clustered in the genome. Genes for resistance (R genes) to diverse pathogens cloned from several species encode proteins that have motifs in common. These motifs indicate that R genes are part of signal-transduction systems. Most of these R genes encode a leucine-rich repeat (LRR) region. Sequences encoding putative solvent-exposed residues in this region are hypervariable and have elevated ratios of nonsynonymous to synonymous substitutions; this suggests that they have evolved to detect variation in pathogen-derived ligands. Generation of new resistance specificities previously had been thought to involve frequent unequal crossing-over and gene conversions. However, comparisons between resistance haplotypes reveal that orthologs are more similar than paralogs implying a low rate of sequence homogenization from unequal crossing-over and gene conversion. We propose a new model adapted and expanded from one proposed for the evolution of vertebrate major histocompatibility complex and immunoglobulin gene families. Our model emphasizes divergent selection acting on arrays of solvent-exposed residues in the LRR resulting in evolution of individual R genes within a haplotype. Intergenic unequal crossing-over and gene conversions are important but are not the primary mechanisms generating variation.Plants, like animals, are continually challenged by a myriad of potential pathogens. There is increasing evidence that defense systems of plants are at least as complex as vertebrate defense systems. Unlike animals, however, plants do not have a circulatory system and therefore cannot rely on a specialized, proliferative immune system. Each plant cell has to be capable of defense, even though this defense is coordinated locally and systemically between cells. There are a variety of types of resistance genes and mechanisms, some induced and some constitutive (for review, see Godiard et al. 1994;Michelmore 1995;Hammond-Kosack and Jones 1997). Often, although not always, disease resistance in plants is determined by single, usually dominant, genes. The recent cloning of several such resistance genes (R genes) is providing insight into their function and evolution. The defense system of plants may be ancient and predate the evolution of the immune system; genes similar to plant R genes have been identified in mammals van der Biezen and Jones 1998).In this review we consider what is known about the genomic organization and evolution of disease resistance genes in plants. The picture that is emerging for the organization and evolution of plant R genes is similar to that of the vertebrate major histocompatibility complex (MHC), T-cell receptor (TCR), and immunoglobulin genes. Therefore, although the specific types of genes involved are different, the evolutionary forces shaping the plant and vertebrate defense systems may be similar. We propose a model for the evolution of plant R genes that is adapted and expanded from a m...

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Section: Clusters Of Resistance Genes Genome Research 1115mentioning

confidence: 99%

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

1998

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“…Based on the pseudo-LRR nature of much of the LHR-ECD and the structure of the LRR protein, ribonuclease inhibitor (Kobe and Disenhofer, 1993), as a template, several laboratories proposed models for the LHR-ECD with 9-14 LRRs (Moyle et al, 1995;Kajava et al, 1995;Jiang et al, 1995;Bhowmick et al, 1996;Couture et al, 1996;Song et al, 2001a), the former of which now appears to be more accurate. Using the threading program PROSPECT (Kim et al, 2003) and the SCOP40 database (Chandonia et al, 2004), we comparatively modeled the LHR-ECD prior to the publication of the FSH-FSHR-ECD complex.…”

Section: The Lhr-ecd: Structure and Hormone Bindingmentioning

confidence: 99%

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

Puett

DeMars

et al. 2007

Molecular and Cellular Endocrinology

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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 cysteinerich 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.

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“…The large ectodomain has been proposed to contain two functional domains: a rigid hormone-binding domain at the N terminus responsible for the high-affinity ligand recognition (8)(9)(10) and an enigmatic juxtamembrane hinge domain responsible for signal specificity (11,12). The structure model of the hormonebinding region was proposed in the mid-1990s (13). The detailed recognition between the ligand and the N-terminal hormonebinding domain of FSHR (FSHR HB ) has been revealed in a complex structure by Fan and Hendrickson (8,14).…”

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confidence: 99%

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

Jiang

Liu

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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236

294

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FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHR ED ), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHR ED . In addition to the known hormone-binding site, FSHR ED provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.F SH is a gonadotropin that stimulates steroidogenesis and gametogenesis in the gonads. Secreted by the anterior pituitary gland, FSH regulates the menstrual cycle and ovarian follicular maturation in women and supports sperm production in men. FSH acts by binding to the FSH receptor (FSHR) on the granulosa cell surface in ovaries and the Sertoli cell surface in testes. The stimulated receptor leads to the dissociation of α-and βγ-subunits of G protein heterotrimer inside the cell. The α-subunit activates adenylyl cyclase, resulting in an increase of cAMP levels, and ultimately leads to the increased steroid production that is necessary for follicular growth and ovulation in women. The free βγ dimers recruit G protein-coupled receptor (GPCR) kinases to the receptor, which, in turn, lead to the recruitment of β-arrestin to the receptor (1). FSH is used clinically for controlled ovarian stimulation in women treated with assisted reproductive technologies and also for the treatment of anovulatory infertility in women and hypogonadotropic hypogonadism in men. The central role of FSH in human reproduction makes its receptor a unique pharmaceutical target in the field of fertility regulation (2-4).The glycoprotein hormone (GPH) family has four members: FSH; two other pituitary hormones, luteinizing hormone and thyroid-stimulating hormone (TSH); and one placental hormone, chorionic gonadotropin. The four members are homologous in sequence, structure, and function. Each member is a heterodimer composed of a common α-subunit and a hormone-specific β-subunit. The crystal structures of FSH and human CG (hCG) revealed that both α-and β-subunits adopt similar folds of cystineknot architecture (5-7). The assembled α-and β-heterodimers bind to their respective receptors with high affinity and hormone specificity, resulting in similar signaling pathways but distinct biological responses.

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Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone–receptor interactions

Cited by 180 publications

References 78 publications

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

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

Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

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