Molecular architecture and biorecognition processes of the cystine knot protein superfamily: part I. The glycoprotein hormones

Hearn, Milton Thomas William; Gomme, Peter T.

doi:10.1002/1099-1352(200009/10)13:5<223::aid-jmr501>3.0.co;2-l

Cited by 112 publications

(40 citation statements)

References 366 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The protein contains four ␣-helices and six conserved cysteine residues, which may form intra-disulfide bonds to give a globular structure. These structural characteristics are common in cytokines (26,27) Fig. 1).…”

Section: Discussionmentioning

confidence: 90%

Cytokine-like 1 (CYTL1) Regulates the Chondrogenesis of Mesenchymal Cells

Kim

Ryoo

Chun

2007

Journal of Biological Chemistry

101

View full text Add to dashboard Cite

To identify novel molecules regulating chondrogenesis and cartilage development, we screened a cartilage-specific expressed sequence tag data base. Cytokine-like 1 (Cytl1), a possible cytokine candidate with unknown function that was originally identified in bone marrow-derived CD34-positive cells, was selected for functional characterization. In view of the initial observation that Cytl1 is predominantly expressed in chondrocytes and cartilage, we investigated its possible role in chondrogenesis and hypertrophic maturation of chondrocytes. Cytl1 expression was very low in mesenchymal cells, dramatically increased during chondrogenesis, and decreased during hypertrophic maturation, both in vivo and in vitro. The role of Cytl1 in chondrogenesis and hypertrophic maturation was examined by treating chondrifying mesenchymal cells with exogenous Cytl1 or ectopic expression of Cytl1. Notably, exogenous Cytl1 caused chondrogenic differentiation of mouse limb bud mesenchymal cells during micromass culture. Lentivirus-mediated overexpression of Cytl1 additionally induced chondrogenic differentiation of mesenchymal cells. However, Cytl1 did not affect the hypertrophic maturation of chondrocytes. Cytl1 exerted its chondrogenic effect via stimulation of Sox9 transcriptional activity. In addition, Cytl1 caused expression of insulin-like growth factor 1, which has a capacity to induce chondrogenesis. Thus, our results collectively suggest that chondrocyte-specific Cytl1 regulates chondrogenesis as a novel autocrine factor, but not hypertrophic maturation of chondrocytes during cartilage development.Cartilage formation during embryonic development begins with the aggregation of mesenchymal cells, which ultimately differentiate into chondrocytes. Differentiated chondrocytes proliferate rapidly and secrete a cartilage-specific extracellular matrix such as type II collagen and sulfated proteoglycan to form cartilage. The cartilage serves as a template for endochondral ossification, which requires the maturation of hypertrophic chondrocytes (1-4). These sequential events during chondrogenesis and cartilage formation are precisely regulated by various growth factors released from cartilage elements and perichondrium. Secreted growth factors exert their effects by modulating intracellular signaling (1, 2). Although several regulatory growth factors have been identified, including bone morphogenetic proteins, fibroblast growth factors, insulin-like growth factor-1 (IGF-1), 2 transforming growth factor-␤, and parathyroid hormone-related peptide, the precise mechanisms of regulation of chondrogenesis and cartilage development remain to be elucidated. In this study, we analyze a cartilagespecific expressed sequence tag (EST) data base in an attempt to identify novel molecules that modulate chondrogenesis and cartilage development.The EST data base provides important information on novel genes displaying tissue-specific expression profiles (5-7). We analyzed the human cartilage UniGene library (8), and selected Cytl1 as a possible candid...

show abstract

Section: Discussionmentioning

confidence: 90%

Cytokine-like 1 (CYTL1) Regulates the Chondrogenesis of Mesenchymal Cells

Kim

Ryoo

Chun

2007

Journal of Biological Chemistry

101

View full text Add to dashboard Cite

show abstract

“…The luteinizing hormone (LH) receptor (LHR) binds two ligands, LH and chorionic gonadotropin (CG), with high affinity and high specificity (Hearn and Gomme, 2000). As a member of the G protein-coupled receptor (GPCR) superfamily, which constitutes roughly 1% of the human genome (Takeda et al, 2002), LHR belongs to the glycoprotein hormone receptor (GPHR) cluster within the rhodopsin family.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…The hormones are heterodimers and share a common α subunit and a hormone-specific β subunit (Hearn and Gomme, 2000). The receptors belong to the rhodopsin family of seven transmembrane G protein-coupled receptors and are characterized by a large ectodomain comprising about half of the receptor and sufficient for high affinity ligand binding.…”

Section: Introductionmentioning

confidence: 99%

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

Meehan¹,

Narayan²

2007

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

Activating mutations in the luteinizing hormone receptor (LHR) gene are one of the most common mutations found in the gonadotropin receptor genes. Human males with these mutations exhibit precocious puberty while females do not have an obvious phenotype. To better understand the pathophysiology of premature LHR activation, transgenic mice have been generated with an activating mutation in LHR and a genetically engineered ligand-activated LHR. This review will summarize the major findings obtained with these two genetically modified mouse models and briefly discuss the similarities and differences between them and with the human phenotype.

show abstract

Molecular architecture and biorecognition processes of the cystine knot protein superfamily: part I. The glycoprotein hormones

Cited by 112 publications

References 366 publications

Cytokine-like 1 (CYTL1) Regulates the Chondrogenesis of Mesenchymal Cells

Cytokine-like 1 (CYTL1) Regulates the Chondrogenesis of Mesenchymal Cells

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

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

Contact Info

Product

Resources

About