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Transthyretin (prealbumin, amyloidosis type I)
Available structures
1bm7, 1bmz, 1bz8, 1bzd, 1bze, 1dvq, 1dvs, 1dvt, 1dvu, 1dvx, 1dvy, 1dvz, 1e3f, 1e4h, 1e5a, 1eta, 1etb, 1f41, 1f86, 1fh2, 1fhn, 1g1o, 1gko, 1ict, 1iii, 1iik, 1ijn, 1qab, 1qwh, 1rlb, 1sok, 1soq, 1tha, 1thc, 1tlm, 1tsh, 1tt6, 1tta, 1ttb, 1ttc, 1ttr, 1tyr, 1tz8, 1u21, 1x7s, 1x7t, 1y1d, 1z7j, 1zcr, 1zd6, 2b14, 2b15, 2b16, 2b77, 2b9a, 2f7i, 2f8i, 2fbr, 2flm, 2g3x, 2g3z, 2g4e, 2g4g, 2g5u, 2g9k, 2gab, 2h4e, 2noy, 2pab, 2rox, 2roy, 2trh, 2try, 5ttr
Identifiers
Symbols TTR; HsT2651; PALB; TBPA
External IDs OMIM176300 MGI98865 HomoloGene317 GeneCards: TTR Gene
RNA expression pattern
PBB GE TTR 209660 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7276 22139
Ensembl ENSG00000118271 ENSMUSG00000061808
UniProt P02766 Q5M9K1
RefSeq (mRNA) NM_000371 NM_013697
RefSeq (protein) NP_000362 NP_038725
Location (UCSC) Chr 18:
27.43 - 27.43 Mb
Chr 18:
20.81 - 20.82 Mb
PubMed search [1] [2]


Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol. This is how transthyretin gained its name, transports thyroxine and retinol.

TTR was originally called prealbumin[1] because it ran faster than albumins on electrophoresis gels.

Contents

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum:

Protein Binding strength Plasma concentration
thyroxine-binding globulin (TBG) highest lowest
transthyretin (TTR) lower higher
albumins poorest much higher

In cerebrospinal fluid it is the primary carrier of T4, as albumin is not present. TTR also acts as a carrier of retinol (vitamin A) through an association with retinol-binding protein (RBP).

Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (diflunisal, flufenamic acid), and toxins (PCB). Since TTR binds promiscuously to many aromatic compounds, and, in general, does not bind T4 in serum, there is speculation that TTR's "true function" is to sweep up toxic and foreign compounds in the bloodstream.

Structure

TTR is a 55-kDa homotetramer with a dimer of dimers configuration that is synthesized in the liver, choroid plexus and retinal pigment epithelium. Each monomer is a 127-residue polypeptide rich in beta sheet structure. Association of two monomers forms an extended beta sandwich. Further association of another identical set of monomers produces the homotetrameric structure. The two thyroxine binding sites per tetramer sit at the interface between the latter set of dimers.

Role in disease

TTR is known to be associated with the amyloid diseases senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC).

TTR is able to deposit as amyloid fibrils, causing neurodegeneration and organ failure. Both point mutations of TTR and wild-type protein are known to deposit as amyloid. A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly found in FAP. A position 122 replacement of valine by isoleucine (TTR V122I) is carried by 3.9% of the African-American population, and is the most common cause of FAC. SSA is estimated to affect over 25% of the population over age 80. Severity of disease varies greatly by mutation, with some mutations causing disease in the first or second decade of life, and others being completely benign. Deposition of TTR amyloid is extracellular. Treatment of TTR amyloid disease is currently limited to liver transplantation as a crude form of gene therapy. Because TTR is primarily produced in the liver, replacement of a liver containing a mutant TTR gene with a normal gene is able to replace the mutant TTR in the body. Certain mutations, however, have been found to have CNS involvement, and due to the blood brain barrier, do not respond to this therapy.

TTR is thought to have beneficial side, however, in binding to the infamous beta-amyloid protein, thereby preventing beta-amyloid's natural tendency to accumulate into the plaques associated with the early stages of Alzheimer's Disease. Preventing plaque formation is thought to enable a cell to rid itself of this otherwise toxic protein form and, thus, help prevent and maybe even treat the disease.

As with most amyloid diseases, it is still unclear whether the deposition of amyloid is the cause of the disease or a correlate of some upstream toxic process. With TTR, it is known that dissociation of the tetramer must occur, followed by misfolding events that ultimately result in amyloid fibrils. New research results point to the oligomers (consisting of max. 8 monomers) to generate the observed cell toxicity.

Transthyretin level in cerebrospinal fluid has also been found to be lower in patients with some neurobiological disorders such as schizophrenia.[2] The reduced level of transthyretin in the CSF may indicate a lower thyroxine transport in brains of patients with schizophrenia.

Because transthyretin is made in part by the choroid plexus, it can be used as an immunohistochemical marker for choroid plexus papillomas.[citation needed]

Nutritional Assessment

In medicine, nutritional status can be assessed by measuring concentrations of transthyretin in the blood. In theory, other transport proteins such as albumin or transferrin could be used but transthyretin is preferred because of its shorter half-life, although this means that its concentration more closely reflects recent dietary intake rather than overall nutritional status.[3] Transthyretin concentration has been shown to be a good indicator of whether or not a malnourished patient will develop refeeding syndrome upon commencement of refeeding, via either the enteral, parenteral or oral routes.[4]

Protein Half-Life (days) Normal Levels Malnutrition
mild moderate severe
Prealbumin 2-4 15.7-29.6 mg/dL 12-15 8-10 <8

Interactions

Transthyretin has been shown to interact with Perlecan.[5]

References

  1. ^ MeSH Prealbumin
  2. ^ Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis ,Huang JTJ, Leweke FM, Oxley D, Wang L, Harris N, et al. (2006) PLoS Med 3(11): e428 PMID 17090210
  3. ^ Shenkin, Alan (2006-12-01). "Serum Prealbumin: Is It a Marker of Nutritional Status or of Risk of Malnutrition?". Clin Chem 52 (12): 2177–2179. doi:10.1373/clinchem.2006.077412. http://www.clinchem.org. Retrieved 2008-09-23. 
  4. ^ Marik, P. E.; M. K. Bedigian (1996-10-01). "Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study". Arch Surg 131 (10): 1043–1047. doi:10.1001/archsurg.131.10.1043. http://archsurg.ama-assn.org/cgi/content/abstract/131/10/1043. Retrieved 2008-09-06. 
  5. ^ Smeland, S; Kolset S O, Lyon M, Norum K R, Blomhoff R (Sep. 1997). "Binding of perlecan to transthyretin in vitro". Biochem. J. (ENGLAND) 326 ( Pt 3): 829–36. ISSN 0264-6021. PMID 9307034. 

Further reading

  • Sakaki Y, Yoshioka K, Tanahashi H, et al. (1990). "Human transthyretin (prealbumin) gene and molecular genetics of familial amyloidotic polyneuropathy". Mol. Biol. Med. 6 (2): 161–8. PMID 2693890. 
  • Saraiva MJ (1995). "Transthyretin mutations in health and disease". Hum. Mutat. 5 (3): 191–6. doi:10.1002/humu.1380050302. PMID 7599630. 
  • Ingenbleek Y, Young V (1994). "Transthyretin (prealbumin) in health and disease: nutritional implications". Annu. Rev. Nutr. 14: 495–533. doi:10.1146/annurev.nu.14.070194.002431. PMID 7946531. 
  • Hesse A, Altland K, Linke RP, et al. (1994). "Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant". British heart journal 70 (2): 111–5. doi:10.1136/hrt.70.2.111. PMID 8038017. 
  • Blanco-Jerez CR, Jiménez-Escrig A, Gobernado JM, et al. (1998). "Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred". Muscle Nerve 21 (11): 1478–85. doi:10.1002/(SICI)1097-4598(199811)21:11<1478::AID-MUS17>3.0.CO;2-X. PMID 9771673. 

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