Structure of the Luteinizing Hormone Receptor Gene and Multiple Exons of the Coding Sequence*

Koo, Yong Bum; Ji, Inhae; Slaughter, R.G.; Ji, Tae H.

doi:10.1210/endo-128-5-2297

Cited by 147 publications

(56 citation statements)

References 51 publications

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“…The first one includes the residues from L264 to R298 that have been previously identified as motif CF3 specifically existing in GPCR proteins (19). The second one extends from residue Y322 to the last residue R366, right before the first transmembrane domain, which is comparable to the N-terminal extracellular loop of rhodopsin attributable to the analogous intronic luteinizing hormone receptor (LHR) sequences corresponding to the promoter and other regulatory regions of the intronless genes of β-adrenergic receptor and rhodopsin (20,21). Our structure shows CF3 is tightly linked to the rhodopsin-like extracellular loop at the Cterminal end via three disulfide bonds between C275, C276, and C292 and C346, C356, and C338, respectively, and the disulfide bond pattern is in agreement with an earlier assignment based on mutagenesis experiments (22).…”

Section: Resultsmentioning

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.

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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Section: Resultsmentioning

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.

236

294

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“…8, row 1) to intron containing NH 2 -terminal protein binding modules conjugated to intronless TM/C domains (16,25) (Fig. 8, row 2) to the intron containing EC/TM/C domains of the CRFR receptor (Fig.…”

Section: Figmentioning

confidence: 99%

The Genomic Structure of the Rat Corticotropin Releasing Factor Receptor

Tsai‐Morris

Buczko

Geng

et al. 1996

Journal of Biological Chemistry

107

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Corticotropin releasing factor (CRF) 1 is a principal neuroregulator within the hypothalamo-pituitary-adrenal axis that coordinates endocrine, behavioral, and autonomic responses to stress. CRF is also an important anti-reproductive hormone that inhibits luteinizing hormone/human chorionic gonadotropin (cAMP)-stimulated androgen production in the rat testis through inhibition of the catalytic subunit of adenylate cyclase (1). High affinity CRF receptors have been characterized in several target tissues including the pituitary (2) and testicular Leydig cells (3). Recent molecular cloning of the pituitary CRF receptor cDNA from human (4), rat (5), and mouse (6) indicate that the expressed protein is a member of the G protein-coupled seven-transmembrane receptor (GPCR) family and has been shown to couple to both adenylate cyclase and phospholipase C (7), stimulating cAMP production and phosphoinositide hydrolysis. The CRF receptor exhibits significant homology to the parathyroid (8) and glucagon (9) receptor family that have been designated as members of Class II (10, 11) in the GPCR superfamily. This class exhibits little primary sequence similarity to the Class I GPCR, and members contain specific conserved amino acid motifs in the extracellular and transmembrane domains (11). In addition, genomic structures of the rat parathyroid (12) and glucagon (13) receptors suggest that some members of the Class II family differ from the catecholamine and the glycoprotein hormone receptor families by the presence of introns in both the NH 2 -terminal extracellular and the transmembrane/cytoplasmic domains.Several variant CRF receptor clones have been identified that carry insertions and deletions of both the extracellular and seven-transmembrane module (7,14). This suggests the presence of multiple introns in the CRF receptor gene and the expression of splice variants that potentially may differ in ligand specificity and modes of signal transduction. This was particularly relevant to our studies in the rat Leydig cell where the CRF receptor did not stimulate cAMP production or appear to be coupled to G s (1, 3) and suggested either a tissue-specific post-translational modification of the CRFR, different G proteins or inhibitors, or the presence of a splice variant of the CRF receptor in the Leydig cell. The structural organization of the CRF receptor gene was determined for subsequent elucidation of isoforms in order to clarify the nature of the Leydig cell receptor. MATERIALS AND METHODS

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“…Important amino acids have been identified for the interaction of the hormone and receptor (23,24). However, the orientation of FSH ␣ and ␤ in the ternary complex of the hormone, exodomain, and endodomain has been a major enigma and difficult to determine.The bulk of the exodomain comprises 8 -9 Leu-rich repeats (LRR) (7,(25)(26)(27)(28), which are flanked by the short upstream N-terminal region and the downstream hinge region. LRRs are thought to form a one-third of a doughnut structure (26 -28).…”

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confidence: 99%

“…The bulk of the exodomain comprises 8 -9 Leu-rich repeats (LRR) (7,(25)(26)(27)(28), which are flanked by the short upstream N-terminal region and the downstream hinge region. LRRs are thought to form a one-third of a doughnut structure (26 -28).…”

mentioning

confidence: 99%

Orientation of Follicle-stimulating Hormone (FSH) Subunits Complexed with the FSH Receptor

Sohn

Youn

Jeoung

et al. 2003

Journal of Biological Chemistry

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Follicle-stimulating hormone (FSH) comprises an ␣ subunit and a ␤ subunit, whereas the FSH receptor consists of two halves with distinct functions: the N-terminal extracellular exodomain and C-terminal membraneassociated endodomain. FSH initially binds to exodomain, and the resulting FSH/exodomain complex modulates the endodomain and generates signal. However, it has been difficult to determine which subunit of FSH contacts the exodomain or endodomain and in what orientation FSH interacts with them. To address these crucial issues, the receptor was Ala-scanned and the hormone subunits were probed with photoaffinity labeling with receptor peptides corresponding to the N-terminal region of the exodomain and exoloop 3 of the endodomain. Our results show that both regions of the receptors are important for hormone binding and signal generation. In addition, the FSH ␤ subunit is specifically labeled with the N-terminal peptide, whereas the ␣ subunit is labeled with the exoloop 3 peptide. These contrasting results show that the FSH ␤ subunit is close to the N-terminal region and that the ␣ subunit is projected toward exoloop 3 in the endodomain. The results raise the fundamental question whether the ␣ subunit, common among the glycoprotein hormones, plays a major role in generating the hormone signal common to all glycoprotein hormones.Follicle-stimulating hormone (FSH) 1 consists of an ␣ subunit of 92 amino acids and ␤ subunit of 111 amino acids. Both of the subunits are necessary for hormone action (1, 2). The crystal structure of human FSH (3) shows that the two subunits are tightly associated in a crescent with the C termini in the concave side and the N termini in the convex side (Fig. 1A). This is essentially the same as the human chorionic gonadotropin structure (4, 5). An exception to this intermingled subunit structure is the two polarized tips of the crescent: the ␣ tip consisting of the ␣ loops 1 and 3 and the ␤ tip of the ␤ loops 1 and 3.In contrast to the tightly held hormone structure, the FSH receptor (FSHR), a G protein-coupled receptor, has two distinct domains as shown in Fig. 1B. The extracellular N-terminal exodomain comprises ϳ350 amino acids, and the membraneassociated C-terminal endodomain with a similar number of amino acids consists of seven transmembrane helices, three exoloops, three cytoloops, and the C-terminal cytoplasmic tail (6 -8). The exodomain binds the hormone with high affinity (9 -16) and selectivity (17), whereas the hormone signal is generated in the endodomain (18 -22). FSH initially interacts with the exodomain, and the resulting FSH/exodomain complex modulates the endodomain to generate hormone signal. Important amino acids have been identified for the interaction of the hormone and receptor (23,24). However, the orientation of FSH ␣ and ␤ in the ternary complex of the hormone, exodomain, and endodomain has been a major enigma and difficult to determine.The bulk of the exodomain comprises 8 -9 Leu-rich repeats (LRR) (7,(25)(26)(27)(28), which are flanked by the short upstream...

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Structure of the Luteinizing Hormone Receptor Gene and Multiple Exons of the Coding Sequence*

Cited by 147 publications

References 51 publications

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

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

The Genomic Structure of the Rat Corticotropin Releasing Factor Receptor

Orientation of Follicle-stimulating Hormone (FSH) Subunits Complexed with the FSH Receptor

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