Molecular and thyroid hormone binding properties of lamprey transthyretins: The role of an N-terminal histidine-rich segment in hormone binding with high affinity

2018 ◽  
Vol 474 ◽  
pp. 74-88 ◽  
Author(s):  
Kentaro Kasai ◽  
Norihito Nishiyama ◽  
Kiyoshi Yamauchi
Keyword(s):  
Thyroid Hormone ◽  
Hormone Binding ◽  
Binding Properties ◽  
High Affinity

scholarly journals Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

2021 ◽  
Author(s):  
Amit Ketkar ◽  
Lane Smith ◽  
Callie Johnson ◽  
Alyssa Richey ◽  
Makayla Berry ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mutation Frequency ◽  
Control Sequence ◽  
Wild Type ◽  
Binding Properties ◽  
High Affinity ◽  
G4 Dna ◽  
G Quadruplex ◽  
Forward Mutagenesis

Abstract We previously reported that human Rev1 (hRev1) bound to a parallel-stranded G-quadruplex (G4) from the c-MYC promoter with high affinity. We have extended those results to include other G4 motifs, finding that hRev1 exhibited stronger affinity for parallel-stranded G4 than either anti-parallel or hybrid folds. Amino acids in the αE helix of insert-2 were identified as being important for G4 binding. Mutating E466 and Y470 to alanine selectively perturbed G4 binding affinity. The E466K mutant restored wild-type G4 binding properties. Using a forward mutagenesis assay, we discovered that loss of hRev1 increased G4 mutation frequency >200-fold compared to the control sequence. Base substitutions and deletions occurred around and within the G4 motif. Pyridostatin (PDS) exacerbated this effect, as the mutation frequency increased >700-fold over control and deletions upstream of the G4 site more than doubled. Mutagenic replication of G4 DNA (±PDS) was partially rescued by wild-type and E466K hRev1. The E466A or Y470A mutants failed to suppress the PDS-induced increase in G4 mutation frequency. These findings have implications for the role of insert-2, a motif conserved in vertebrates but not yeast or plants, in Rev1-mediated suppression of mutagenesis during G4 replication.

Role of thyroglobulin endocytic pathways in the control of thyroid hormone release

2000 ◽  
Vol 279 (5) ◽  
pp. C1295-C1306 ◽  
Author(s):  
Michele Marinò ◽  
Robert T. McCluskey
Keyword(s):  
Thyroid Hormone ◽  
Intracellular Trafficking ◽  
Fluid Phase ◽  
Thyroid Stimulating Hormone ◽  
Asialoglycoprotein Receptor ◽  
Hormone Release ◽  
Hormone Stimulation ◽  
High Affinity ◽  
Endocytic Pathways

Thyroglobulin (Tg), the thyroid hormone precursor, is synthesized by thyrocytes and secreted into the colloid. Hormone release requires uptake of Tg by thyrocytes and degradation in lysosomes. This process must be precisely regulated. Tg uptake occurs mainly by micropinocytosis, which can result from both fluid-phase pinocytosis and receptor-mediated endocytosis. Because Tg is highly concentrated in the colloid, fluid-phase pinocytosis or low-affinity receptors should provide sufficient Tg uptake for hormone release; high-affinity receptors may serve to target Tg away from lysosomes, through recycling into the colloid or by transcytosis into the bloodstream. Several apical receptors have been suggested to play roles in Tg uptake and intracellular trafficking. A thyroid asialoglycoprotein receptor may internalize and recycle immature forms of Tg back to the colloid, a function also attributed to an as yet unidentified N-acetylglucosamine receptor. Megalin mediates Tg uptake by thyrocytes, especially under intense thyroid-stimulating hormone stimulation, resulting in transcytosis of Tg from the colloid to the bloodstream, a function that prevents excessive hormone release.

scholarly journals An Essential Role of Domain D in the Hormone-Binding Activity of Human β1 Thyroid Hormone Nuclear Receptor

1991 ◽  
Vol 5 (4) ◽  
pp. 485-492 ◽  
Author(s):  
Kwang-Huei Lin ◽  
Clifford Parkison ◽  
Peter McPhie ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Essential Role ◽  
Binding Activity ◽  
Hormone Binding

scholarly journals Effect of deglycosylation on the structure and hormone-binding activity of the lutropin receptor

1988 ◽  
Vol 256 (3) ◽  
pp. 719-724 ◽  
Author(s):  
K P Keinänen
Keyword(s):  
Polyacrylamide Gel Electrophoresis ◽  
Binding Activity ◽  
Hormone Binding ◽  
Binding Properties ◽  
Lh Receptor ◽  
High Affinity ◽  
Human Choriogonadotropin ◽  
Lutropin Receptor ◽  
Membrane Bound ◽  
Polypeptide Backbone

Affinity-purified rat ovarian lutropin (LH) receptor is a single 90 kDa polypeptide which binds to immobilized lectins, indicating that the receptor is a glycoprotein [Keinänen, Kellokumpu, Metsikkö & Rajaniemi (1987) J. Biol. Chem. 262, 7920-7926]. In the present study the glycoprotein nature of the rat ovarian LH receptor was investigated in order to determine the contribution of the glycan moiety to receptor's size and hormone-binding properties. Treatment of the 125I-labelled purified LH receptor with neuraminidase and peptide N-glycosidase F resulted in a decrease in size of LH receptor from 90 kDa to 79 kDa and 62 kDa respectively, as assessed by SDS/polyacrylamide-gel electrophoresis. Endo-alpha-N-acetylgalactosaminidase treatment did not affect the electrophoretic mobility of the intact or neuraminidase-treated LH receptor. Subjecting the membrane-bound LH receptor to similar enzymic treatments followed by ligand blotting showed that the 79 kDa and 62 kDa forms are capable of specific hormone binding. Furthermore, intact and peptide N-glycosidase F-treated membranes bound 125I-labelled human choriogonadotropin with similar affinities. These data suggest that molecular mass of the polypeptide backbone of the LH receptor is 62 kDa. The receptor contains N-glycosidically linked oligosaccharide chains with terminal sialic acid residues, with little or no O-linked oligosaccharide. N-Linked carbohydrate is not required for specific high-affinity hormone binding.

scholarly journals Biochemistry, pharmacology and physiological role of sex hormone binding globulin

2018 ◽  
Vol 49 (3) ◽  
pp. 189
Author(s):  
D. KOURETAS (Δ. ΚΟΥΡΕΤΑΣ) ◽  
V. LALIOTIS (Β. ΛΑΛΙΩΤΗΣ) ◽  
O. ANTONOGLOU (Ο. ΑΝΤΩΝΟΓΛΟΥ)
Keyword(s):  
Sex Steroids ◽  
Physiological Role ◽  
Sex Hormone Binding Globulin ◽  
Target Cells ◽  
Hormone Binding ◽  
High Affinity ◽  
Dimeric Protein ◽  
Steroid Binding ◽  
Steroid Binding Protein

Sex steroid binding protein (SBP) is a plasma protein that specifically binds sex steroids with high affinity. It is synthesized in the liver and circulates in the plasma of many species including human, monkey, cattle, dog, cat and others. SBP is a dimeric protein with a Mr ranging between 84-9Θ KDa and binds one steroid molecule per dimer. Its expression is regulated by many hormones and estradiol promotes while testosterone inhibits its expression. Its physiological role is not known completely, but it is likely to control at least the bioavailable levels of circulating steroids. Experimental evidence from our laboratory and others supports the dogma that non-bound steroids are free to enter the target cells and act. After the discovery of SBP-membrane receptor, it seems that SBP serves also other biological role except that of binding steroids. All recent reports are discussed.

scholarly journals Genetic dissection of thyroid hormone receptor beta: identification of mutations that separate hormone binding and transcriptional activation.

1995 ◽  
Vol 15 (3) ◽  
pp. 1499-1512 ◽  
Author(s):  
R Uppaluri ◽  
H C Towle
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Ligand Binding ◽  
Reporter Gene ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Receptor Activation ◽  
Hormone Binding ◽  
D Region

The thyroid hormone receptors (TR) are members of the nuclear receptor family of ligand-mediated transcription factors. The large region of TR that lies C-terminal to its DNA-binding domain subserves functions of ligand binding, dimerization, and transactivation. Little is known regarding the structural or functional determinants of these processes. We have utilized genetic screening in the yeast Saccharomyces cerevisiae to identify residues involved in these functions. Random mutations of the rat TR beta 1 isoform between amino acid residues 179 and 456 were screened, and mutants with reduced hormone-dependent activation of reporter gene activity were isolated. In this paper we describe the characterization of a class of mutants that exhibit a dissociation between hormone binding and transcriptional activation. These mutants retained hormone binding (> 15% of the wild-type level) yet failed to transactivate a reporter gene. A number of these mutations occurred within the D region, which links the DNA-binding and ligand-binding domains of the receptor. One subset of these mutations abrogated DNA binding, supporting a role of the D region in this process. The remainder retain DNA binding and thus highlight residues critical for receptor activation. In addition, an unexpected group of "superactivator" mutations that led to enhanced hormone-dependent activation in S. cerevisiae were found. These mutations localized to the carboxy-terminal portion of the receptor in a region which contains elements conserved across the superfamily of nuclear receptors. The hormone-dependent phenotype of these superactivator mutations suggests an important role of this segment in ligand-mediated transcriptional activation.

The role of thyroid hormone autoantibodies in serum transport

1989 ◽  
Vol 121 (4) ◽  
pp. 551-559 ◽  
Author(s):  
Susan Copping ◽  
Peter G. H. Byfield
Keyword(s):  
Thyroid Hormone ◽  
Equilibrium Distribution ◽  
Reverse Flow ◽  
Specific Binding ◽  
Equilibrium System ◽  
Binding Properties ◽  
Thyroxine Binding Globulin ◽  
Thyroid Hormone Autoantibodies

Abstract. Eleven sera known to contain thyroid hormone autoantibodies were analysed by reverse-flow electrophoresis for the equilibrium distribution of thyroid hormones between these autoantibodies and the three normal binding proteins found in serum. The binding properties of the autoantibodies determined in vitro did not necessarily predict their contribution to transport in serum of T4 and T3. Some could both bind in vitro and transport in serum. Others were able to bind both hormones but transported only one. However, some autoantibodies could be specific, binding and transporting one hormone only. In some sera, the autoantibody was the dominant transport protein having drawn hormone from thyroxine-binding globulin which is normally the most important. The autoantibodies were not saturated even in euthyroid individuals, indicating that they bind hormone reversibly and are a part of an equilibrium system.

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