Thyroid Hormone Serum Transport Proteins: Structure, Properties, Genes and Transcriptional regulation

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INTRODUCTION

Thyroid hormone (TH) effects are dependent on the quantity of the hormone that reaches peripheral tissues and the availability of unaltered TH receptors in the cells nuclei. Since TH enters the cell unbound, the concentration of free rather than total hormone reflects more accurately the activity level of TH-dependent processes. Under normal conditions, changes in free hormone level are adjusted by appropriate stimulation or suppression of hormone secretion and disposal.

Total TH concentration in serum is normally kept at a level proportional to the concentration of carrier proteins, and appropriate to maintain a constant free hormone level. Most carrier protein dependent alterations in total hormone concentration in serum are due to quantitative changes in the hormone-binding proteins and less commonly to changes in affinity for the hormone. Since wide fluctuations in the concentration of TH carrier proteins does not alter the hormonal economy or metabolic status of the subject (1), their function is open to speculation. They are responsible for the maintenance of a large extrathyroidal pool of TH of which only the minute, <0.5 % fraction of free hormone is immediately available to tissues. It can be estimated that in the absence of binding proteins the small extrathyroidal T 4 pool would be significantly reduced, if not completely depleted in a matter of hours following a sudden cessation of hormone secretion. In contrast, in the presence of normal concentrations of T 4 -binding serum proteins, and in particular thyroxine-binding globulin (TBG), a 24-h arrest in hormonal secretion would bring about a decrease in the concentration of T 4 and T 3 in the order of only 10 and 40 per cent, respectively. Thus it seems logical to assume that one of the functions of T 4 -binding proteins in serum is to safeguard the body from the effects of abrupt fluctuations in hormonal secretion. The second likely function of T 4 -binding serum proteins is to serve as an additional protection against iodine wastage by imparting macromolecular properties to the small iodothyronine molecules, thus limiting their urinary loss (2). The lack of high affinity T 4 -binding proteins in fish (3),for example, may be teleologically attributed to the greater iodine abundance in their natural habitat. Liver perfusion studies suggest a third function, that facilitating the uniform cellular distribution of T 4 , allowing for changes in the circulating thyroid hormone level to be rapidly communicated to all cells within organ tissues (4). A fourth function, modeled after the corticosteroid-binding globulin (5), is targeting the amount of hormone delivery by site specific, enzymatic, alteration of TBG. Indeed neutrophil derived elastase transforms TBG into a heat resistant, relaxed, form with reduced T 4 -binding affinity (6). TBG was found to have a putative role on the testicular size of the boar. In fact Meishan pigs with histidine rather than an asparagine in codon 226 have a TBG with lower affinity for T 4 , smaller testes and earlier onset of puberty (7, 8).

In normal man, approximately 0.03 per cent of the total serum T 4 , and 0.3 per cent of the total serum T 3 are present in free or unbound form (3, 9). The major serum thyroid hormone-binding proteins are thyroxine-binding globulin [TBG or thyropexin], transthyretin [TTR or thyroxine-binding prealbumin (TBPA)], and albumin (HAS, human serum albumin) (10). Several other serum proteins, in particular high density lipoproteins, bind T 4 and T 3 as well as rT 3 (9, 11) but their contribution to the overall hormone transport is negligible in both physiological and pathological situations. In term of their relative abundance in serum, HSA is present at approximately 100-fold the molar concentration of TTR and 2,000-fold that of TBG. However, from the view point of the association constants for T 4 , TBG has highest affinity, which is 50-fold higher than that of TTR and 7,000-fold higher that of HSA. As a result TBG binds 75% of serum T 4 , while TTR and HSA binds only 20% and 5%, respectively (Table 1). From evolutionary point of view, the three iodothyronine-binding serum proteins developed in reverse order of their affinity for T 4 , HSA being the oldest (12).

Table 1. Some Properties and Metabolic Parameters of the Prinicpal Thyroid Hormone-Binding Proteins in Serum

TBG TTR ALB
Molecular weight (k daltons) 54* 55 6
Structure Monomer Tetramer Monomer
Carbohydrate content (%) 20
Number of binding sites for T 4 and T 3 1 2 Several
Association constant, Ka (M-1)
For T 4 1 x 10 10 2 x 10 8 ** 1.5 x 10 6 **
For T 3 1x 10 9 1 x 10 6 2 x 10 5
Concentration in serum (mean normal, mg/liter) 16 250 40,000
Relative distribution of T 4 and T 3 in serum (%)
T 4 75 20 5
T 3 75 <5 20
In-Vivo Survival
Half-life (days) 5*** 2 15
Degradation rate (mg/day) 15 650 17,000
*Apparent molecular weight on acrylamide gel electrophoresis 60 k daltons**Value given is for the high affinity binding site only.***Longer under the influence of estrogen.Reproduced with permission from Hayashi and Refetoff, Molecular Endocrinology: Basic concepts and clinical correlations, Raven Press Ltd. 1995

The existence of inherited TH-binding protein abnormalities was recognized 1959, with the report of a family with TBG-excess (13) but it took 30 years before the first mutation in a defective was identified (14). Genetic variants of TH-binding proteins having different capacity or affinity for their ligands than the common type protein result in euthyroid hyper- or hypo-iodothyroninemia. The techniques of molecular biology have traced these abnormalities to polymorphisms or mutations in genes encoding TBG and TTR and HSA (see Chapter 16C) .

1. THYROXINE-BINDING GLOBULIN (TBG)

The molecule, structure and physical properties: TBG is a 54 kD acidic glycoprotein migrating in the inter-  -globulin zone on conventional electrophoresis, at pH 8.6. The term, thyroxine-binding globulin, is a misnomer since the molecule also binds T 3 and reverse T 3 . It was first recognized to serve as the major thyroid hormone transport protein in serum in 1952 (15). Since TBG binds 75% of serum T 4 and T 3 , quantitative and qualitative abnormalities of this protein have most profound effects on the total iodothyronine levels in serum. Its primary structure was deduced in 1989 from the nucleotide sequence of a partial TBG cDNA and an overlapping genomic DNA clones (16). However, it took 17 years to characterize its three dimensional structure by crystallographic analysis (17).

TBG is synthesized in the liver as single polypeptide chain of 415 amino acids. The mature molecule, minus the signal peptide, is composed of 395 amino acids (44 kD) and four heterosaccharide units with 5 to 9 terminal sialic acids. The carbohydrate chains are not required for hormone binding but are important for the correct post-translational folding and secretion of the molecule (18, 19) and are responsible for the multiple TBG isoforms (microheterogeneity) present on isoelectric focusing (20)(15). The isoelectric point of normal TBG ranges from pH 4.2 to 4.6, however, this increases to 6 when all sialic acid residues are removed.

The protein is very stable when stored in serum, but rapidly loses its hormone binding properties by denaturation at temperatures above 55°C and pH below 4. The half-life of denaturation at 60°C is approximately 7 min but association with T 4 increases the stability of TBG (21-23). TBG can be measured by immunometric techniques or saturation analysis using one of its iodothyronine ligands (23-25).

The tertiary structure of TBG was solved by cocrystallizing the in-vitro synthesized nonglycosylated molecule with T 4 and speculations regarding the properties of TBG and its variants have been confirmed (17, 26). The molecule caries T 4 in a surface pocket held by a series of hydrophobic interactions with underlying residues and hydrogen bonding of the aminoproprionate of T 4 with adjacent residues. TBG differs from other members of the SERPIN family in having the upper half of the main ß-sheet completely opened. This allows the reactive center peptide loop to move in and out of the sheet, resulting in binding and release of the ligand without cleavage of TBG. Thus the molecule can assume a high-affinity and a low-affinity conformation, a model proposed earlier by Grasberger et al (24). This reversibility is due to the unique presence of P8 proline in TBG, rather than a threonine in all other SERPINs, limiting loop insertion. The coordinated movements of the reactive loop, hD, and the hormone binding site allow the allosteric regulation of hormone release.

figure2a

Structure of the TBG molecule: Reactive loop (in yellow). Insertion occurs following its cleavage by proteases to give an extra strand in the main sheet of the molecule but the T4-binding site can still retain its active conformation. This is in keeping with other findings showing that the binding and release of T4 is not due to a switch from an on to an off conformation but rather results from an equilibrated change in plasticity of the binding site. So the S-to-R change in TBG results in a 6 -fold decrease but not a total loss of affinity. The important corollary is that that the release of thyroxine is a modulated process as notably seen in response to changes in temperature (Qi et al. 2011, J Biol Chem 286: 16163-73).

Gene structure and transcriptional regulation: The molecule is encoded by a single gene copy located in the long arm of the human X-chromosome (Xq22.2) (27, 28). The gene consists of 5 exons spanning 5.5kbp (Fig. 1). The first exon is a small and non-coding. It is preceded by a TATAA box and a sequence of 177 nucleotides containing an hepatocyte transcription factor-1 (HNF-1) binding motif that imparts to the gene a strong liver specific transcriptional activity (29). The numbers and size of exons, their boundaries and types of intron splice junctions as well as the amino acid sequences they encode are similar to those of other members of the serine protease inhibitor (SERPIN) family, to which TBG belongs (29). These include cortisol-binding globulin and the serine protease inhibitors,  1-antitrypsin (  1AT) and  1-antichymotrypsin (  1ACT).

Figure 1. A. Genomic organization and chromosomal localization of thyroid hormone serum binding proteins. Filled boxes represent exons. Location of initiation codons and termination codons are indicated by arrows. B. Structure of promoter regions with the location of cis-acting transcriptional regulatory elements. Reproduced with permission from Hayashi and Refetoff, Molecular Endocrinology: Basic concepts and clinical correlations, Raven Press Ltd. 1995.

Biological properties: The TBG molecule has a single iodothyronine binding site with affinity slightly higher for T 4 than for T 3 (30) (Table 1). Optimal binding activity requires the presence of the L-alanine side chain, an unsubstituted 4′-hydroxyl group, a diphenyl ether bridge, and halogen (I or Br) constituents at the 3,5,3′ and 5′ positions (31). Compared to L-T 4 , rT 3 binds to TBG with ~40% higher affinity, D-T 4 with half that of the L-isomer and tetraiodothyroacetic acid with ~25%. A number of organic compounds compete with thyroid hormone-binding to TBG. Most notable are: 5,5 diphenylhydantoin (32), 1,8-anilinonaphthalenesulfonic acid and salicylates (33). While reversible flip-flop conformational changes of TBG allow for binding and release of the hormone ligand, cleavage of the molecule by leukocyte elastase. produces a permanent change in the properties molecule. this modified form has reduced T 4 -binding and increased heat stability (6).

Denatured TBG does not bind iodothyronines but can be detected with antibodies that recognize the primary structure of the molecule (23). In euthyroid adults with normal TBG concentration, about one-third of the molecules carry thyroid hormone, mainly T 4 . When fully saturated, it carries about 20 µg of T 4 /dl of serum. The biologic half-life is about 5 days, and the volume of distribution is similar to that of albumin (34, 35) (Table 1). TBG is cleared by the liver. Loss of sialic acid accelerates its removal through interaction with the asialo-glycoprotein receptors reducing the half live by 500-fold (21). However, it is unknown whether desialylation is a required in the normal pathway of TBG metabolism.

Physiology

TBG concentration in the serum of normal adults ranges from 1.1 to 2.1 mg/dl (180 – 350 nM), 14 – 26 µg T 4 /dl in terms of maximal T 4 -binding capacity. The protein is present in serum of the 12th week old fetus and in the newborn until 2-3 years of age it is about 1.5 times the normal adult concentration (36-38). TBG levels decline slightly reaching a nadir during mid-adulthood and tend to rise with further advance in age (39). Variable amounts of TBG, though much smaller than those in serum, have been detected in amniotic fluid (40), cerebrospinal fluid (41) and urine (42).

Estrogen excess, either from an endogenous source (hydatidiform mole, estrogen-producing tumors, etc) or exogenous (therapeutic or birth control use) is the most common cause of increased serum TBG concentration. The level of several other serum proteins such as corticosteroid-binding globulin, testosterone-binding globulin, ceruloplasmin, and transferrin, are also increased (43). This effect of estrogen is mediated through an increase in the complexity of the oligosaccharide residues in TBG together with an increase in the number of sialic acids resulting in prolonged biological half life (44, 45). Androgens and anabolic steroids produce an opposite effect (46, 47). Although sex hormones affect the serum level of TBG, gender differences are small except during pregnancy during which concentrations are on the average 2.5-fold the normal value (25, 48).

Acquired TBG abnormalities

Altered synthesis, degradation, or both are responsible for the majority of acquired TBG abnormalities (35). Severe terminal illness is undoubtedly the most common cause for acquired decrease in TBG concentration. Interleukin-6, a suppresser of acute phase reactants, is a candidate for mediation of this effect (49). In vivo studies in man showed a reduction in the turnover of TBG in hypothyroidism and an increase in hyperthyroidism (34, 35). Thus, alterations in the degradation rate, rather than changes in the rate of synthesis, may be responsible for the changes of TBG concentration observed in these two conditions.

Partially desialylated TBG, has slow electrophoretic mobility (sTBG, not to be confused with the variant TBG-S), and was found in the serum of some patients with sever liver disease (50) and may be present in relatively higher proportion than TBG in serum of patients with a variety of non-thyroidal illnesses (51). This is not surprising considering that sTBG has a very short half life in serum being rapidly removed by the asialoglycoprotein receptors, present in abundance on liver cells (21, 52).

Patients with the carbohydrate-deficient glycoprotein (CDG) syndrome show a characteristic cathodal shift in the relative proportion of TBG isoforms compatible with diminished sialic acid content (53). This inherited syndrome presenting psychomotor retardation, cerebellar hypoplasia, peripheral sensorimotor neuropathy, and variably, retinitis pigmentosa, skeletal abnormalities and lipodystrophy (54), manifests also abnormalities of charge and mass in a variety of serum glycoproteins (55).

2. TRANSTHYRETIN (TTR)

The molecule, structure and physical properties: TTR is a 55kD tetramer which is highly acidic although it contains no carbohydrate. Formerly known as thyroxine-binding prealbumin (TBPA), for its electrophoretic mobility anodal to albumin, was first recognized to bind T 4 in 1958 (56). Subsequently it was demonstrated that TTR also forms a complex with retinol-binding protein and thus plays a role in the transport of vitamin A (retinol, or trans retinoic acid) (57, 58).

TTR circulates in blood as a stable tetramer of identical subunits, each containing 127 amino acids (59). Although the tetrameric structure of the molecule was demonstrated by genetic studies (60, 61), detailed structural analysis is available through X-ray crystallography (62, 63). Each TTR subunit has 8 ß-strands four of which form the inner sheet and four the outer sheet. The four subunits form a symmetrical ß-barrel structure with a double trumpeted hydrophobic channel that traverses the molecule forming the two iodothyronine binding sites. Despite the apparent identity of the two iodothyronine binding sites, TTR usually binds only one T 4 molecule because the binding affinity of the second site is greatly reduced through a negative cooperative effect (64). The TTR tetramer can bind four molecules of RBP that do not interfere with T 4 -binding, and vice versa (65). TTR can be measured by densitometry after its separation from the other serum proteins by electrophoresis, by hormone saturation, and by immunoassays.

Gene structure and transcriptional regulation: TTR is encoded by a single gene copy located on human chromosome 18 (18q11.2-12.1) (59, 66) (Fig. 1). The gene consists of 4 exons spanning for 6.8kbp. Knowledge about the transcriptional regulation of the human TTR gene comes from studies of the mouse gene structural and sequence homology of which extends to the promoter region (67, 68). In both species a TATAA box and binding sites for HNF-1, 3 and 4 are located within 150 bp from the transcription start site.

Although TTR in serum originates from the liver (69), TTR mRNA is also found in kidney cells the choroid plexus, meninges, retina, placenta, pancreatic islet cells and fetal intestine (70-73). TTR constitutes up to 25% of the total protein present in ventricular cerebrospinal fluid where it binds 80% of T 4 (74) .

Biological properties: Despite the 20-fold higher concentration of TTR in serum relative to that of TBG, it plays a lesser role in iodothyronine transport. In the presence of normal levels of TBG, wide fluctuations in TTR concentration or its removal from serum by specific antibodies has little influence on the concentration of free T 4 (75). Some of the properties of TTR are summarized in Table 1.

The first T 4 molecule binds to TTR with a Ka of about 100 fold higher than that for HSA and about 100-fold lesser than that for TBG. Properties necessary for optimal binding activity include iodines at the 3′ and 5′ positions and a desamino acid side chain which explain the lower T 3 and higher tetraiodoacetic acid affinities relative to that of T 4 (31, 76). Non-iodothyronine ligands are also differentially bound, the most notable example being the flavonoid compounds which have a markedly higher binding affinity for TTR than for TBG (77). Among drugs that compete with T 4 -binding to TTR are ethacrynic acid, salicylates, 2,4-dinitrophenol, and penicillin (78, 79). Barbital also inhibits iodothyronine binding to TTR.

Only 0.5% of the circulating TTR is occupied by T 4 . TTR has a relatively rapid turnover (t1/2 = 2 days) and a distribution space similar to that of HSA and TBG (80, 81) except that it also exists in CSF. Hence, acute diminution in the rate of synthesis is accompanied by a rapid decrease of its concentration in serum.

Physiology

Normal average concentration in serum is 25 mg/dl, and corresponds to a maximal binding capacity of approximately 300 µg T 4 /dl. Changes in TTR concentration have relatively little effect on the serum concentration of serum iodothyronines (75, 82). There is a distinct reciprocal relationship between acquired changes in TBG and TTR concentration related to gender, age, glucocorticoids, estrogen and androgens (39, 48, 83-85).

Acquired TTR abnormalities

The reduction or serum TTR concentration surpasses that of TBG in major illness, nephrotic syndrome, liver disease, cystic fibrosis, hyperthyroidism, and protein-calorie malnutrition (10, 86-88). Increased serum TTR concentration can occur in some patients with islet cell carcinoma (89). Studies on the metabolism of TTR in man, utilizing radioiodinated purified human TTR, indicate that diminished TTR concentration associated with severe illness or stress is due to a decrease in the rate of synthesis or an increase in the rate of degradation, or both (80, 81).

3. HUMAN SERUM ALBUMIN (HSA)

The molecule, structure and physical properties: HSA is a 66.5 kD protein synthesized by the liver. It is composed of 585 amino acids with high content of cystines and charged amino acids but no carbohydrate (90). The three domains of the molecule can be conceived as three tennis balls packaged in a cylindrical case.

Gene structure and transcriptional regulation: HSA is encoded by a single gene copy located on human chromosome 4 (4q11-q13) (91). The gene contains 15 exons, 14 of which are coding (92) (Fig. 1). The promoter region of the HSA gene has been most intensive studied. The transcriptional regulation has been best characterized in rodents that share 90% sequence homology with the corresponding human gene, including a distal enhancer element 10 kbp upstream from the promoter region (93). Binding sites for hepatocyte enriched nuclear proteins, such as HNF-1, C/EBP, and DBP have been identified (94-96).

Biological properties: HSA associates with a wide variety of substances including hormones and drugs possessing a hydrophobic region, and thus the association of TH to HSA can be viewed as nonspecific. Of the several iodothyronine-binding sites on the HSA molecule, only one has a relatively high affinity for T 4 and T 3 . Yet these are 10,000-fold inferior to those of TBG (24). Fatty acids and chloride ions decrease their binding to HSA (24). The biologic t1/2 of HSA is relatively long (97). Some of its properties are summarized in Table 1.

More than half of the total protein content in serum is HSA. As a result, it is the principal contributor to the maintenance of the colloid osmotic pressure (90). It has been suggested that HSA synthesis my be, in part, regulated by a feedback mechanism involving alteration in the colloid osmotic pressure. Indeed, down-regulation of HSA gene expression has been recently observed during the infusion of macromolecules in the rat (98).

Physiology

Because of the low affinity and despite the high capacity of HSA for iodothyronines, its contribution to thyroid hormone transport is relatively minor. Thus, even the most marked fluctuations of serum HSA concentration, including analbuminemia, have no significant effects on thyroid hormone levels (99).

Lipoproteins

Lipoproteins bind T 4 , and to some extent T 3 (9, 100). The affinity for T4-binding is similar to that of TTR. These proteins are estimated to transport roughly 3% of the total T 4 and perhaps as much as 6% of the total T 3 in serum. The binding site of apolipoprotein A1 is a region of the molecule that is distinct from that portion which binds to the cellular lipoprotein receptors, and the physiological role of such binding is still unclear.

Acknowledgments

Supported in part by grants DK-15070, DK-20595 and RR-04999 from the National Institutes of Health (USA).

REFERENCES

1. Refetoff S 1989 Inherited thyroxine-binding globulin (TBG) abnormalities in man. Endocr Rev 10:275-293

2. Chan V, Besser GM, Landon J 1972 Effects of oestrogen on urinary thyroxine excretion. Brit Med J 4:699-701

3. Refetoff S, Robin NI, Fang VS 1970 Parameters of thyroid function in serum of 16 selected vertebrate species: A study of PBI, serum T4, free T4, and the pattern of T4 and T3 binding to serum proteins. Endocrinology 86:793-805

4. Mendel CM, Weisinger RA, Jones AL, Cavalieri RR 1987 Thyroid hormone-binding proteins in plasma facilitate uniform distribution of thyroxine within tissues: A perfused rat liver study. Endocrinology 120:1742-1749

5. Pemberton PA, Stein PE, Pepys MB, Potter JM, Carell RW 1988 Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336:257-258

6. Janssen OE, Golcher HMB, Grasberger H, Saller B, Mann K, Refetoff S 2002 Characterization of thyroxine-binding globulin cleaved by human leukocyte elastase. J Clin Endocrinol Metab 87:1217-1222

7. Ford JJ, Rohrer GA, Nonneman DJ, Lunstra DD, Wise TH 2010 Association of allelic variants of thyroid-binding globulin with puberty in boars and responses to hemicastration. Anim Reprod Sci 119:228-234

8. Nonneman D, Rohrer GA, Wise TH, Lunstra DD, Ford JJ 2005 A variant of porcine thyroxine-binding globulin has reduced affinity for thyroxine and is associated with testis size. Biol Reprod 72:214-220

9. Freeman T, Pearson JD 1969 The use of quantitative immunoelectrophoresis to investigate thyroxine-binding human serum proteins. Clin Chim Acta 26:365-368

10. Oppenheimer JH 1968 Role of plasma proteins in the binding, distribution, and metabolism of the thyroid hormones. N Engl J Med 278:1153-1162

11. Benvenga S, Gregg RE, Robbins J 1988 Binding of thyroid hormone to human plasma lipoproteins. J Clin Endocrinol Metab 67:6-16

12. Yamauchi K, Ishihara A 2009 Evolutionary changes to transthyretin: developmentally regulated and tissue-specific gene expression. FEBS J 276:5357-5366

13. Beierwaltes WH, Robbins J 1959 Familial increase in the thyroxine-binding sites in serum alpha globulin. J Clin Invest 38:1683-1688

14. Mori Y, Seino S, Takeda K, Flink IL, Murata Y, Bell GI, Refetoff S 1989 A mutation causing reduced biological activity and stability of thyroxine-binding globulin probably as a result of abnormal glycosylation of the molecule. Mol Endocrinol 3:575-579

15. Robbins J 1992 Thyroxine transport and the free hormone hypothesis. J Clin Endocrinol Metab 131:546-547

16. Flink IL, Bailey TJ, Gustefson TA, Markham BE, Morkin E 1986 Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: Close homology to the serine antiproteases. Proc Natl Acad Sci U S A 83:7708-7712

17. Zhou A, Wei Z, Read RJ, Carrell RW 2006 Structural mechanism for the carriage and release of thyroxine in the blood. Proc Natl Acad Sci U S A 103:13321-13326

18. Murata Y, Magner JA, Refetoff S 1986 The role of glycosylation in the molecular conformation and secretion of thyroxine-binding globulin. Endocrinology 118:1614-1621

19. Kambe F, Seo H, Mori Y, Murata Y, Janssen OE, Refetoff S, Matsui N 1992 An additional carbohydrate chain in the variant thyroxine-binding globulin-Gary (TBG Asn-96 ) impairs its secretion. Mol Endocrinol 6:443-449

20. Gärtner R, Henze R, Horn K, Pickardt CR, Scriba PC 1981 Thyroxine-binding globulin: Investigation of microheterogeneity. J Clin Endocrinol Metab 52:657-664

21. Refetoff S, Fang VS, Marshall JS 1975 Studies on human thyroxine-binding globulin (TBG): IX. Some physical, chemical and biological properties of radioiodinated TBG and partially desialylated TBG (STBG). J Clin Invest 56:177-187

22. Grimaldi S, Edelhoch H, Robbins J 1982 Effects of thyroxine binding on the stability, conformation, and fluorescence properties of thyroxine-binding globulin. Biochemistry (Mosc) 21:145-150

23. Refetoff S, Murata Y, Vassart G, Chandramouli V, Marshall JS 1984 Radioimmunoassays specific for the tertiary and primary structures of thyroxine-binding globulin (TBG): Measurement of denatured TBG in serum. J Clin Endocrinol Metab 59:269-277

24. Tabachnick M, Giorgio NA, Jr. 1964 Thyroxine-protein interactions. II. The binding of thyroxine and its analogues to human serum albumin. Arch Biochem Biophys 105:563-569

25. Refetoff S, Hagen S, Selenkow HA 1972 Estimation of the T4 binding capacity of serum TBG and TBPA by a single T4 load ion exchange resin method. J Nucl Med 13:2-12

26. Qi X, Loiseau F, Chan WL, Yan Y, Wei Z, Milroy LG, Myers RM, Ley SV, Read RJ, Carrell RW, Zhou A 2011 Allosteric modulation of hormone release from thyroxine and corticosteroid-binding globulins. J Biol Chem 286:16163-16173

27. Trent JM, Flink IL, Morkin E, Van Tuinen P, Ledbetter DH 1987 Localization of the human thyroxine-binding globulin gene to the long arm of the X chromosome (Xq21-22). Am J Hum Genet 41:428-435

28. Mori Y, Miura Y, Oiso Y, Seo H, Takazumi K 1995 Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization. Hum Genet 96:481-482

29. Hayashi Y, Mori Y, Janssen OE, Sunthornthepvarakul T, Weiss RE, Takeda K, Weinberg M, Seo H, Bell GI, Refetoff S 1993 Human thyroxine-binding globulin gene: Complete sequence and transcriptional regulation. Mol Endocrinol 7:1049-1060

30. Hocman G 1981 Human thyroxine binding globulin. Rev Physiol Biochem Pharmacol 81:45-88

31. Cody V 1980 Thyroid hormone interactions: Molecular conformation, protein binding and hormone action. Endocr Rev 1:140-166

32. Oppenheimer JH, Tavernetti RR 1962 Displacement of thyroxine from human thyroxine-binding globulin by analogues of hydantoin. Steric aspects of the thyroxine-binding site. J Clin Invest 41:2213-2220

33. Larsen PR 1972 Salicylate-induced increases in free triiodothyronine in human serum: Evidence of inhibition of triiodothyronine binding to thyroxine-binding gloublin and thyroxine-binding prealbumin. J Clin Invest 51:1125-1134

34. Cavalieri RR, McMahon FA, Castle JN 1975 Preparation of 125 I-labeled human thyroxine-binding alpha globulin and its turnover in normal and hypothyroid subjects. J Clin Invest 56:79-87

35. Refetoff S, Fang VS, Marshall JS, Robin NI 1976 Metabolism of thyroxine-binding globulin (TBG) in man: Abnormal rate of synthesis in inherited TBG deficiency and excess. J Clin Invest 57:485-495

36. Andreoli M, Robbins J 1962 Serum proteins and thyroxine-protein interaction in early human fetuses. J Clin Invest 41:1070-1077

37. Robbins J, Nelson JH 1958 Thyroxine-binding by serum protein in pregnancy and in the newborn. J Clin Invest 37:153-159

38. Stubbe P, Gatz J, Heidemann P, Muhlen ARG, Hesch R 1978 Thyroxine-binding globulin, triiodothyronine, thyroxine and thyrotropin in newborn infants and children. Horm Metab Res 10:58-61

39. Braverman LE, Dawber NA, Ingbar SH 1966 Observations concerning the binding of thyroid hormones in sera of normal subjects of varying ages. J Clin Invest 45:1273-1279

40. Burman KD, Read J, Dimond RC, Strum D, Wright FD, Patow W, Earll JM, Wartofsky L 1976 Measurement of 3,3′,5′-Triiodothyroinine (reverse T3), 3,3′-L-diiodothyronine, T3 and T4 in human amniotic fluid and in cord and maternal serum. J Clin Endocrinol Metab 43:1351-1359

41. Hagen GA, Elliott WJ 1973 Transport of thyroid hormones in serum and cerebrospinal fluid. J Clin Endocrinol Metab 37:415-422

42. Gavin LA, McMahon FA, Castle JN, Cavalieri RR 1979 Detection of a thyroxine-binding protein physicochemically similar to serum thyroxine-binding globulin in normal human urine. J Clin Endocrinol Metab 48:843-847

43. Doe RP, Mellinger GT, Swaim WR, Seal JS 1967 Estrogen dosage effects on serum proteins: A longitudinal study. J Clin Endocrinol Metab 27:1081-1086

44. Ain KB, Mori Y, Refetoff S 1987 Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689-696

45. Ain KB, Refetoff S, Sarne DH, Murata Y 1988 Effect of estrogen on the synthesis and secretion of thyroxine-binding globulin (TBG) by a human hepatoma cell line, Hep G2. Mol Endocrinol 2:313-323

46. Federman DD, Robbins J, Rall JE 1958 Effects of methyl testosterone on thyroid function, thyroxine metabolism, and thyroxine-binding protein. J Clin Invest 37:1024-1030

47. Barbosa J, Seal US, Doe RP 1971 Effects of anabolic steroids on haptoglobin, orosomucoid, plasminogen, fibrinogen, transferrin, ceruloplasmin, alpha-1-antitrypsin, beta- glucuronidase and total serum proteins. J Clin Endocrinol Metab 33:388-398

48. Braverman LE, Foster AE, Ingbar SH 1967 Sex-related differences in the binding in serum of thyroid hormone. J Clin Endocrinol Metab 27:227-232

49. Bartalena L, Farsetti A, Flink IL, Robbins J 1992 Effects of interleukin-6 on the expression of thyroid-hormone binding protein genes in cultured hepatoblastoma-derived (Hep G2) cells. Mol Endocrinol 6:935-942

50. Marshall JS, Pensky J, Green AM 1972 Studies on human thyroxine-binding globulin. IV. The nature of slow thyroxine-binding globulin. J Clin Invest 51:3173-3181

51. Reilly CP, Wellby ML 1983 Slow thyroxine binding globulin in the pathogenesis of increased dialysable fraction of thyroxine in nonthyroidal illnesses. J Clin Endocrinol Metab 57:15-18

52. Marshall JS, Green AM, Pensky J, Williams S, Zinn A, Carlson DM 1974 Measurement of circulating desialylated glycoproteins and correlation with hepatocellular damage. J Clin Invest 54:555-562

53. Macchia PE, Harrison HH, Scherberg NH, Sunthornthepvarakul T, Jaeken J, Refetoff S 1995 Thyroid function tests and characterization of thyroxine-binding globulin in the carbohydrate-deficient glycoprotein syndrome type I. J Clin Endocrinol Metab 80:3744-3749

54. Jaeken J, Hagberg B, Strømme P 1991 Clinical presentation and natural course of the carbohydrate-deficient glycoprotein syndrome. Acta Pediatr Scand Suppl 375:6-13

55. Stibler H, Jaeken J, Kristiansson B 1991 Biochemical characteristics and diagnosis of the carbohydrate-deficient glycoprotein syndrome. Acta Pediatr Scand Suppl 375:21-31

56. Ingbar SH 1958 A thyroxine-binding protein of human plasma. Endocrinology 63:256-259

57. Kanai M, Raz A, Goodman D 1968 Retinol-binding protein: The transport protein for vitamin A in human plasma. J Clin Invest 47:2025-2044

58. Peterson PA 1971 Characteristics of a vitamin A-transporting protein complex occurring in human serum. J Biol Chem 246:34-43

59. Tsuzuki T, Mita S, Maeda S, Araki S, Shimada K 1985 Stucture of human prealbumin gene. J Biol Chem 260:12224-12227

60. Alper CA, Robin NI, Refetoff S 1969 Genetic polymorphism of Rhesus thyroxine-binding prealbumin: Evidence for tetrameric structure in primates. Proc Natl Acad Sci U S A 63:775-781

61. Bernstein RS, Robbins J, Rall JE 1970 Polymorphism of monkey thyroxine-binding prealbumin (TBPA): Mode of inheritance and hybridization. Endocrinol 86:383-390

62. Rerat C, Schwick HG 1967 Données cristallographiques sur la préalbumine du plasma sanguin. Acta Cryst 22:441

63. Blake CCF, Oatley SJ 1977 Protein-DNA and protein-hormone interactions in prealbumin: A model of the thyroid hormone nuclear receptor? Nature (London) 268:115-120

64. Irace G, Edelhoch H 1978 Thyroxine induced conformational changes in prealbumin. Biochemistry (Mosc) 17:5729-5733

65. van Jaarsveld PP, Edelhoch H, Goodman DS, Robbins J 1973 The interaction of human plasma retinol binding protein with prealbumin. J Biol Chem 248:4698-4705

66. LeBeau MM, Geurts van Kessel G 1991 Report of the committee on the genetic costitution of chromosome 18. Cytogenet Cell Genet 58:739-750

67. Costa RH, Grayson DR, Darnell Jr JE 1989 Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and a 1-antitrypsin. Mol Cell Biol 9:1415-1425

68. Sladeck FM, Zhong R, Lai E, Darnell Jr. JE 1990 Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Gene Dev 4:2353-2365

69. Knowles BB, Howe CC, Aden DP 1980 Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science 209:497-499

70. Dickson PW, ., Howlett GJ, Schreiber G 1985 Rat transthyretin (prealbumin): molecular cloning, nucleotide sequence, and gene expression in liver and brain. J Biol Chem 260:8214-

71. Dickson PW, Aldred AR, Marley PD, Bannister D 1985 Rat choroid plexus specializes in the synthesis and secretion of transthyretin (prealbumin). J Biol Chem 261:3475-

72. Jacobsson B, Pettersson T, Sandstedt B, Carlstrom A 1979 Prealbumin in the islets of Langerhans. Int Res Commun Syst Med Sci 7:590-

73. Richardson SJ 2009 Evolutionary changes to transthyretin: evolution of transthyretin biosynthesis. FEBS J 276:5342-5356

74. Herbert J, Wilcox JN, Pham K-TC, Fremeau Jr RT, Zeviani M, Dwork A, Soprano DR, Makover A, Goodman DS, Zimmerman EA, Roberts JL, Schon EA 1986 Transthyretin: a choroid plexus-specific transport protein in human brain. Neurology 36:900-911

75. Woeber KA, Ingbar SH 1968 The contribution of thyroxine-binding prealbumin to the binding of thyroxine in human serum, as assessed by immunoadsorption. J Clin Invest 47:1710-1721

76. Pages RA, Robbins J, Edelhoch H 1973 Binding of thyroxine and thyroxine analogs to human serum prealbumin. Biochem 12:2773-2779

77. Lueprasitsakul W, Alex S, Fang SL, Pino S 1990 Flavonoid administration immediately displaces thyroxine (T4) from serum transthyretin, increases serum free T4, and decreases thyrotropin in the rat. Endocrinology 126:2890-

78. Wolff J, Standaert ME, Rall JE 1961 Thyroxine displacement from serum proteins and depression of serum protein-bound iodine by certain drugs. J Clin Invest 40:1373-1379

79. Munro SL, Lim CF, Hall JG, Barlow JW, Craik DJ, Topliss DJ, Stockigt JR 1989 Drug competition for thyroxine binding to transthyretin (Prealbumin): Comparison with effects on thyroxine-binding globulin. J Clin Endocrinol Metab 68:1141-1147

80. Socolow EL, Woeber KA, Purdy RH, Holloway MT, Ingbar SH 1965 Preparation of I 131 -labeled human serum prealbumin and its metabolism in normal and sick patients. J Clin Invest 44:1600

81. Oppenheimer JH, Surks MI, Bernstein G, Smith JC 1965 Metabolism of iodine-131-labeled thyroxine-binding prealbumin in man. Science 149:748-751

82. Braverman LE, AvRuskin T, Cullen MJ, Vagenakis AG, Ingbar SH 1971 Effects of norethandrolone on the transport and peripheral metabolism of thyroxine in patients lacking thyroxine-binding globulin. J Clin Invest 50:1644-1649

83. Braverman LE, Ingbar SH 1967 Effects of norethandrolone on the transport in serum and peripheral turnover of thyroxine. J Clin Endocrinol Metab 27:389-396

84. Oppenheimer JH, Werner SC 1966 Effect of prednisone on thyroxine-binding proteins. J Clin Endocrinol Metab 26:715-721

85. Man EB, Reid WA, Hellegers AE, Jones WS 1969 Thyroid function in human pregnancy. III. Serum thyroxine-binding prealbumin (TBPA) and thyroxine-binding globulin (TBG) of pregnant women aged 14 through 43 years. Am J Obst Gyn 103:338-347

86. Inada M, Sterling K 1967 Thyroxine turnover and transport in Laennec’s cirrhosis of the liver. J Clin Invest 46:1275-1282

87. Ingenbleek Y, deVisscher M, deNayer P 1972 Measurement of prealbumin as index of protein-calorie malnutrition. Lancet 2:106-108

88. Smith FR, Underwood BA, Denning CR, Varma A, Goodman DSC 1972 Depressed plasma retinol-binding protein levels in cystic fibrosis. J Lab Clin Med 80:423-433

89. Rajatanavin R, Liberman C, Lawrence GD, D’Arcangues CM, Young RA, Emerson CH 1985 Euthyroid hyperthyroxinemia and thyroxine-binding prealbumin excess in islet cell carcinoma. J Clin Endocrinol Metab 61:17-21

90. Peters T, Jr. 1985 Serum albumin. Adv Prot Chem 37:161-245

91. Murray JC, Van Ommen GJB 1991 Report of the committee on the genetic constitution of chromosome 4. Cytogenet Cell Genet 58:231-260

92. Dugaiczyk A, Law SW, Dennison OE 1982 Nucleotide sequence and the encoded amino acids of human serum albumin mRNA. Proc Natl Acad Sci U S A 79:71-75

93. Hayashi Y, Chan J, Nakabayashi H, Hashimoto T, Tamaoki T 1992 Identification and characterization of two enhancers of the human albumin gene. J Biol Chem 267:14580-14585

94. Gereghini S, Raymondjean M, Carranca AG, Heibomel P, Yaniv M 1987 Factors involved in control of tissue-specific expression of albumin gene. Cell 50:627-638

95. Johnson PF 1990 Transcriptional activators in hepatocytes. Cell Growth Differ 1:47-52

96. Rey-Campos J, Yaniv M 1992 Regulation of albumin gene expression. Amsterdam: Elsevier Science Publishers

97. Beeken WL, Volwilier W, Goldsworthy PD, Garby LE, Reynolds WE, Stogsdill R, Stemler RS 1962 Studies of I 131 -albumin catabolism and distribution in normal young male adults. J Clin Invest 41:1312-1333

98. Pietrangelo A, Panduro A, Chowdhury JR, Shafritz DA 1992 Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat. J Clin Invest 89:1755-1760

99. Hollander CS, Bernstein G, Oppenheimer JH 1968 Abnormalities of thyroxine binding in analbuminemia. J Clin Endocrinol Metab 28:1064-1066

100. Benvenga S, Robbins J 1993 Lipoprotein-thyroid hormone interactions. TEM 4:194-198