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

Abstract

In this review article, the reader is introduced to recent advances in our knowledge on a subset of the cystine knot superfamily of homo- and hetero-dimeric proteins, from the perspective of the endocrine glycoprotein hormone family of proteins: follitropin (FSH), Iutropin (LH), thyrotropin. (TSH) and chorionic gonadotropin (CG). Subsequent papers will address the structure-function behaviour of other members of this increasingly significant family of proteins, including various members of the transforming growth factor-beta (TGF-beta) family of proteins, the activins, inhibins, bone morphogenic growth factor, platelet derived growth factor-beta, nerve growth factor and more than 35 other proteins with similar topological features. In the present review article, specific emphasis has been placed on advances with the glycoprotein hormones (GPHs) that have facilitated greater insight into their physiological functions, molecular structures and most importantly the basis of the molecular recognition events that lead to the formation of hetero-dimeric structures as well as their specific and selective recognition by their corresponding receptors and antibodies. Thus, this review article focuses on the structural motifs involved in receptor recognition and the current techniques available to identify these regions, including the role of immunological methodology, peptide fragment design and synthesis and mutagenesis to delineate their structure-function relationships and molecular recognition behaviour.

A novel function of bursicon in stimulation of vitellogenin expression in black tiger shrimp, Penaeus monodon

“…This was similar to other cystine knot-containing proteins including glycoprotein hormone family, transforming growth factor beta and bone morphogenetic protein (BMP) antagonist (Roch and Sherwood, 2014). Moreover, additional disulfide bond between C2 and C8 formed a seat-belt like structure, which was similar to that of human CGβ (Hearn and Gomme, 2000) and Drosophila bursicon (Luo et al, 2005).…”

“…The up-regulation of Vg induced by bursicon at 48 h after treatment might suggest that bursicon is required to mediate the stimulation of vitellogenesis. Although there was no evidence revealing downstream process activated by bursicon in crustaceans, one of the roles of other glycoprotein hormones, especially FSH was to regulate the expression and increase the activity of a steroidogenic enzyme aromatase that converts androgens to estrogens (Erickson and Hsueh, 1978;Hearn and Gomme, 2000;Parakh et al, 2006). Moreover, vertebrate steroid hormone such as 17β-estradiol was also demonstrated to stimulate Vg synthesis in the oocyte of M. japonicus (Yano and Hoshino, 2006) as well as increase Vg level in the hemolymph of the crayfish, Cherax albidus (Coccia et al, 2010).…”

A novel function of bursicon in stimulation of vitellogenin expression in black tiger shrimp, Penaeus monodon

“…This was similar to other cystine knot-containing proteins including glycoprotein hormone family, transforming growth factor beta and bone morphogenetic protein (BMP) antagonist (Roch and Sherwood, 2014). Moreover, additional disulfide bond between C2 and C8 formed a seat-belt like structure, which was similar to that of human CGβ (Hearn and Gomme, 2000) and Drosophila bursicon (Luo et al, 2005).…”

“…The up-regulation of Vg induced by bursicon at 48 h after treatment might suggest that bursicon is required to mediate the stimulation of vitellogenesis. Although there was no evidence revealing downstream process activated by bursicon in crustaceans, one of the roles of other glycoprotein hormones, especially FSH was to regulate the expression and increase the activity of a steroidogenic enzyme aromatase that converts androgens to estrogens (Erickson and Hsueh, 1978;Hearn and Gomme, 2000;Parakh et al, 2006). Moreover, vertebrate steroid hormone such as 17β-estradiol was also demonstrated to stimulate Vg synthesis in the oocyte of M. japonicus (Yano and Hoshino, 2006) as well as increase Vg level in the hemolymph of the crayfish, Cherax albidus (Coccia et al, 2010).…”

Functional and Evolutionary Analysis of Flatfish Gonadotropin Receptors Reveals Cladal- and Lineage-Level Divergence of the Teleost Glycoprotein Receptor Family1

“…The significance of this finding is not yet clear, but it can be postulated that additional binding sites within the interaction domain of the exposed receptor surface could have implications for the selectivity and/or affinity of the cognate hormone. We find that unlike mammalian FSHR, which responds exclusively to FSHb [77], sole Fshra responds to both sbFshsc and sbLhsc when expressed in X. laevis oocytes. The use of this surrogate system demonstrated that both sole fshra and lhcgrba encode functional receptors, because the level of intracellular cAMP increased in Fshra-and Lhcgrba-expressing oocytes when exposed to hCG and recombinant piscine Fsh and Lh in a dose-dependent manner.…”

Consequences of Single-Chain Translation on the Structures of Two Chorionic Gonadotropin Yoked Analogs in α-β and β-α Configurations

“…The crystal structures of hCG (4, 5) and hFSH (7) have provided considerable insight into the structure-function relationships of this family of cystine knot-containing hormones. Indeed, the growth factor-like cystine knot is fundamental to the structural integrity of the hormones by acting as a molecular scaffold on which the rest of the molecule is defined and thus was suggested to be integral to the proper presentation of hormone to receptor (1).…”

A novel function of bursicon in stimulation of vitellogenin expression in black tiger shrimp, Penaeus monodon

“…This was similar to other cystine knot-containing proteins including glycoprotein hormone family, transforming growth factor beta and bone morphogenetic protein (BMP) antagonist (Roch and Sherwood, 2014). Moreover, additional disulfide bond between C2 and C8 formed a seat-belt like structure, which was similar to that of human CGβ (Hearn and Gomme, 2000) and Drosophila bursicon (Luo et al, 2005).…”

“…The up-regulation of Vg induced by bursicon at 48 h after treatment might suggest that bursicon is required to mediate the stimulation of vitellogenesis. Although there was no evidence revealing downstream process activated by bursicon in crustaceans, one of the roles of other glycoprotein hormones, especially FSH was to regulate the expression and increase the activity of a steroidogenic enzyme aromatase that converts androgens to estrogens (Erickson and Hsueh, 1978;Hearn and Gomme, 2000;Parakh et al, 2006). Moreover, vertebrate steroid hormone such as 17β-estradiol was also demonstrated to stimulate Vg synthesis in the oocyte of M. japonicus (Yano and Hoshino, 2006) as well as increase Vg level in the hemolymph of the crayfish, Cherax albidus (Coccia et al, 2010).…”

Functional and Evolutionary Analysis of Flatfish Gonadotropin Receptors Reveals Cladal- and Lineage-Level Divergence of the Teleost Glycoprotein Receptor Family1

“…The significance of this finding is not yet clear, but it can be postulated that additional binding sites within the interaction domain of the exposed receptor surface could have implications for the selectivity and/or affinity of the cognate hormone. We find that unlike mammalian FSHR, which responds exclusively to FSHb [77], sole Fshra responds to both sbFshsc and sbLhsc when expressed in X. laevis oocytes. The use of this surrogate system demonstrated that both sole fshra and lhcgrba encode functional receptors, because the level of intracellular cAMP increased in Fshra-and Lhcgrba-expressing oocytes when exposed to hCG and recombinant piscine Fsh and Lh in a dose-dependent manner.…”

Consequences of Single-Chain Translation on the Structures of Two Chorionic Gonadotropin Yoked Analogs in α-β and β-α Configurations

“…The crystal structures of hCG (4, 5) and hFSH (7) have provided considerable insight into the structure-function relationships of this family of cystine knot-containing hormones. Indeed, the growth factor-like cystine knot is fundamental to the structural integrity of the hormones by acting as a molecular scaffold on which the rest of the molecule is defined and thus was suggested to be integral to the proper presentation of hormone to receptor (1).…”

A novel function of bursicon in stimulation of vitellogenin expression in black tiger shrimp, Penaeus monodon

“…This was similar to other cystine knot-containing proteins including glycoprotein hormone family, transforming growth factor beta and bone morphogenetic protein (BMP) antagonist (Roch and Sherwood, 2014). Moreover, additional disulfide bond between C2 and C8 formed a seat-belt like structure, which was similar to that of human CGβ (Hearn and Gomme, 2000) and Drosophila bursicon (Luo et al, 2005).…”

“…The up-regulation of Vg induced by bursicon at 48 h after treatment might suggest that bursicon is required to mediate the stimulation of vitellogenesis. Although there was no evidence revealing downstream process activated by bursicon in crustaceans, one of the roles of other glycoprotein hormones, especially FSH was to regulate the expression and increase the activity of a steroidogenic enzyme aromatase that converts androgens to estrogens (Erickson and Hsueh, 1978;Hearn and Gomme, 2000;Parakh et al, 2006). Moreover, vertebrate steroid hormone such as 17β-estradiol was also demonstrated to stimulate Vg synthesis in the oocyte of M. japonicus (Yano and Hoshino, 2006) as well as increase Vg level in the hemolymph of the crayfish, Cherax albidus (Coccia et al, 2010).…”

Functional and Evolutionary Analysis of Flatfish Gonadotropin Receptors Reveals Cladal- and Lineage-Level Divergence of the Teleost Glycoprotein Receptor Family1

“…The significance of this finding is not yet clear, but it can be postulated that additional binding sites within the interaction domain of the exposed receptor surface could have implications for the selectivity and/or affinity of the cognate hormone. We find that unlike mammalian FSHR, which responds exclusively to FSHb [77], sole Fshra responds to both sbFshsc and sbLhsc when expressed in X. laevis oocytes. The use of this surrogate system demonstrated that both sole fshra and lhcgrba encode functional receptors, because the level of intracellular cAMP increased in Fshra-and Lhcgrba-expressing oocytes when exposed to hCG and recombinant piscine Fsh and Lh in a dose-dependent manner.…”

Consequences of Single-Chain Translation on the Structures of Two Chorionic Gonadotropin Yoked Analogs in α-β and β-α Configurations

“…The crystal structures of hCG (4, 5) and hFSH (7) have provided considerable insight into the structure-function relationships of this family of cystine knot-containing hormones. Indeed, the growth factor-like cystine knot is fundamental to the structural integrity of the hormones by acting as a molecular scaffold on which the rest of the molecule is defined and thus was suggested to be integral to the proper presentation of hormone to receptor (1).…”