Thyroxine-binding globulin

SERPINA7
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2CEO, 2RIV, 2RIW, 2XN3, 2XN5, 2XN6, 2XN7, 4X30, 4YIA
Identifiers
Aliases	SERPINA7, TBG, serpin family A member 7, Thyroxine-binding globulin，TBG, TBGQTL
External IDs	OMIM: 314200 MGI: 3041197 HomoloGene: 20113 GeneCards: SERPINA7
Gene location (Human)
Chr.	X chromosome (human)
End	106,038,727 bp
Gene location (Mouse)
Chr.	X chromosome (mouse)
End	139,085,236 bp
Gene ontology
Molecular function	• serine-type endopeptidase inhibitor activity;
Cellular component	• extracellular exosome; • extracellular region; • extracellular space;
Biological process	• thyroid hormone transport; • negative regulation of endopeptidase activity;
	Sources:Amigo / QuickGO
Orthologs
	6906
	331535
	ENSG00000123561
	ENSMUSG00000031271
	P05543
	P61939
	NM_000354
	NM_177920; NM_001382371; NM_001382372
	NP_000345
	NP_808588; NP_001369300; NP_001369301
	Wikidata
View/Edit Human	View/Edit Mouse

Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the SERPINA7 gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃) in the bloodstream. Of these three proteins, TBG has the highest affinity for T₄ and T₃ but is present in the lowest concentration relative to transthyretin and albumin, which also bind T3 and T4 in circulation. Despite its low concentration, TBG carries the majority of T₄ in the blood plasma. Due to the very low concentration of T₄ and T₃ in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T₄/T₃. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.

Role in diagnosis

Thyroxine-binding globulin tests are sometimes used to find the cause of raised or lowered levels of thyroid hormone. This is done by measuring resin binding to labeled thyroid hormone, which happens only when the labeled thyroid hormone is free.

The patient's serum is mixed with the labeled thyroid hormone; next, the resin is added to the whole mixture to measure the amount of free labeled thyroid hormone. So, for instance, if the patient is truly hypothyroid, and TBG levels are normal, then there are many sites open for binding on the TBG, since the total thyroid hormone level is low. Therefore, when the labeled hormone is added, it will bind mostly to the TBG, leaving little of it left for binding to the resin. In contrast, however, if the patient is truly hyperthyroid, and TBG levels are normal, the patient's endogenous hormone will saturate the TBG binding sites more, leaving less room for the labeled hormone, which allows greater binding to the resin.

In patients who are truly hypo- or hyperthyroid, TBG testing is not very useful. However, if total thyroid hormone levels point to hypothyroidism or hyperthyroidism in the absence of accompanying symptoms, the utility of TBG testing becomes more evident, since TBG production can be modified by other factors such as estrogen levels, corticosteroid levels, or liver failure. If, for example, the TBG level is high, which can occur when estrogen levels are high, the TBG will bind more thyroid hormone, decreasing the free hormone available in the blood, which leads to stimulation of TSH, and the production of more thyroid hormone. In this case, the total thyroid hormone level will be high. And so, when labeled hormone is added, since TBG is so high, once equilibrium between the binding of endogenous thyroid hormone and the labeled hormone is achieved, less free labeled hormone will be available for uptake into the resin. On the converse, in the presence of corticosteroids, which lower TBG levels, the total thyroid hormone (bound and free) in the blood will be low. Thus, when the labeled hormone is added, since so little TBG is available in the blood, after equilibrium is achieved, only a small portion of it will bind, leaving plenty available for uptake by the resin

Cheng SY (1978). "Partial amino acid sequence of human thyroxine-binding globulin. Further evidence for a single polypeptide chain". Biochem. Biophys. Res. Commun. 79 (4): 1212–8. doi:10.1016/0006-291X(77)91135-4. PMID 414747.
Shirotani T, Kishikawa H, Wake N, et al. (1993). "Thyroxine-binding globulin variant (TBG-Kumamoto): identification of a point mutation and genotype analysis of its family". Endocrinol. Jpn. 39 (6): 577–84. doi:10.1507/endocrj1954.39.577. PMID 1294376.
Bertenshaw R, Sarne D, Tornari J, et al. (1992). "Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions". Biochim. Biophys. Acta. 1139 (4): 307–10. doi:10.1016/0925-4439(92)90105-v. PMID 1515456.
Bertenshaw R, Takeda K, Refetoff S (1991). "Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotide substitutions". Am. J. Hum. Genet. 48 (4): 741–4. PMC 1682945. PMID 1901689.
Imamura S, Mori Y, Murata Y, et al. (1991). "Molecular cloning and primary structure of rat thyroxine-binding globulin". Biochemistry. 30 (22): 5406–11. doi:10.1021/bi00236a012. PMID 1903654.
Janssen OE, Takeda K, Refetoff S (1991). "Sequence of the variant thyroxine-binding globulin (TBG) in a Montreal family with partial TBG deficiency". Hum. Genet. 87 (2): 119–22. doi:10.1007/BF00204164. PMID 1906047. S2CID 9241072.
Yamamori I, Mori Y, Seo H, et al. (1991). "Nucleotide deletion resulting in frameshift as a possible cause of complete thyroxine-binding globulin deficiency in six Japanese families". J. Clin. Endocrinol. Metab. 73 (2): 262–7. doi:10.1210/jcem-73-2-262. PMID 1906892.
Li P, Janssen OE, Takeda K, et al. (1991). "Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene". Metab. Clin. Exp. 40 (11): 1231–4. doi:10.1016/0026-0495(91)90221-h. PMID 1943753.
Waltz MR, Pullman TN, Takeda K, et al. (1990). "Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks". J. Endocrinol. Invest. 13 (4): 343–9. doi:10.1007/bf03349576. PMID 2115061. S2CID 22555365.
Mori Y, Takeda K, Charbonneau M, Refetoff S (1990). "Replacement of Leu227 by Pro in thyroxine-binding globulin (TBG) is associated with complete TBG deficiency in three of eight families with this inherited defect". J. Clin. Endocrinol. Metab. 70 (3): 804–9. doi:10.1210/jcem-70-3-804. PMID 2155256.
Takeda K, Mori Y, Sobieszczyk S, et al. (1989). "Sequence of the variant thyroxine-binding globulin of Australian aborigines. Only one of two amino acid replacements is responsible for its altered properties". J. Clin. Invest. 83 (4): 1344–8. doi:10.1172/JCI114021. PMC 303827. PMID 2495303.
Mori Y, Seino S, Takeda K, et al. (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 (3): 575–9. doi:10.1210/mend-3-3-575. PMID 2501669.
Flink IL, Bailey TJ, Gustafson TA, et al. (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 (20): 7708–12. Bibcode:1986PNAS...83.7708F. doi:10.1073/pnas.83.20.7708. PMC 386790. PMID 3094014.
Janssen OE, Chen B, Büttner C, et al. (1996). "Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago". J. Biol. Chem. 270 (47): 28234–8. doi:10.1074/jbc.270.47.28234. PMID 7499319.
Mori Y, Miura Y, Oiso Y, et al. (1995). "Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization". Hum. Genet. 96 (4): 481–2. doi:10.1007/BF00191811. PMID 7557975. S2CID 33967655.
Miura Y, Mori Y, Yamamori I, et al. (1994). "Sequence of a variant thyroxine-binding globulin (TBG) in a family with partial TBG deficiency in Japanese (TBG-PDJ)". Endocr. J. 40 (1): 127–32. doi:10.1507/endocrj.40.127. PMID 7951486.
Hayashi Y, Mori Y, Janssen OE, et al. (1993). "Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation". Mol. Endocrinol. 7 (8): 1049–60. doi:10.1210/me.7.8.1049. PMID 8232304.
Akbari MT, Kapadi A, Farmer MJ, et al. (1994). "The structure of the human thyroxine binding globulin (TBG) gene". Biochim. Biophys. Acta. 1216 (3): 446–54. doi:10.1016/0167-4781(93)90013-4. PMID 8268226.
Mori Y, Miura Y, Takeuchi H, et al. (1996). "Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families". J. Clin. Endocrinol. Metab. 80 (12): 3758–62. doi:10.1210/jc.80.12.3758. PMID 8530630.
Carvalho GA, Weiss RE, Vladutiu AO, Refetoff S (1998). "Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene". Thyroid. 8 (2): 161–5. doi:10.1089/thy.1998.8.161. PMID 9510125.

External links

Overview of all the structural information available in the PDB for UniProt: P05543 (Thyroxine-binding globulin) at the PDBe-KB.

1 2 3 GRCh38: Ensembl release 89: ENSG00000123561 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031271 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000123561 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031271 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

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Serpins
inhibitory	Alpha 1-antichymotrypsin Alpha 1-antitrypsin Alpha 2-antiplasmin Antithrombin C1-inhibitor Heparin cofactor II Protein C inhibitor Plasminogen activator inhibitor-1 Plasminogen activator inhibitor-2 Protein Z-related protease inhibitor SERPINA1 SERPINA2 SERPINA3 SERPINA4 SERPINA5 SERPINA9 SERPINA14 SERPINB1 SERPINB2 SERPINB3 SERPINB4 SERPINB5 SERPINB6 SERPINB7 SERPINB8 SERPINB9 SERPINB10 SERPINB13 SERPINC1 SERPIND1 SERPINE1 SERPINE2 SERPINE2 SERPINF1 SERPING1 SERPINH1 SERPINI1 SERPINI2
Cross class inhibitory	MENT SCCA-1 CrmA
noninhibitory	Heat shock protein 47 Maspin Ovalbumin Transcortin Thyroxine-binding globulin Angiotensinogen PEDF
see also disorders of globin and globulin proteins

Proteins: carrier proteins
Fatty acid	FABP1 FABP2 FABP3 FABP4 FABP5 FABP6 FABP7
Hormone	peptide hormone: Follistatin Growth hormone binding protein Insulin-like growth factor binding protein IGFBP1 IGFBP2 IGFBP3 IGFBP4 IGFBP5 IGFBP6 IGFBP7 Neurophysins Neurophysin I II steroid hormone: Sex hormone binding globulin/Androgen binding protein Transcortin Thyroxine-binding globulin Transthyretin
Metal/element	calcium Calcium-binding protein Calmodulin-binding proteins copper Ceruloplasmin iron Iron-binding proteins Transferrin receptor
Vitamin	Retinol binding protein 1 2 3 4 Transcobalamin
Pigment	Plant Light-Harvesting Complex Orange Carotenoid Protein Phycobiliprotein Photosynthetic Reaction Centers Phytochrome Rhodopsin
Other	Acyl carrier protein Adaptor protein Cholesterylester transfer protein F-box protein GTP-binding protein Latent TGF-beta binding protein Major urinary proteins Membrane transport protein Odorant binding protein

Thyroxine-binding globulin

Role in diagnosis

Further reading

External links