Transthyretin (TTR or TBPA) is a transport protein in the plasma and

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

that transports the thyroid hormone

thyroxine Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its acti ...

(T₄) and

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and ...

to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol''. The liver secretes TTR into the blood, and the

choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...

secretes TTR into the

. TTR was originally called prealbumin (or thyroxine-binding prealbumin) because it migrated faster than

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

on electrophoresis gels. Prealbumin was felt to be a misleading name, it is not a synthetic precursor of albumin. The alternative name TTR was proposed by DeWitt Goodman in 1981. Human transthyretrin protein is encoded by the ''TTR'' gene, which is located on the long arm of chromosome 18, in cytogenetic band 18q12.1.

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum: In cerebrospinal fluid TTR is the primary carrier of T₄. TTR also acts as a carrier of

(vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF. Less than 1% of TTR's T₄ binding sites are occupied in blood, which is taken advantage of below to prevent TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue. Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as

resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol or polyphenol and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacterium, ba ...

), drugs ( tafamidis, diflunisal, and flufenamic acid), and toxicants ( PCB).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127-residue

polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

rich in

beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

structure. Association of two monomers via their edge beta-strands forms an extended beta sandwich. Further association of two of these dimers in a face-to-face fashion produces the homotetrameric structure and creates the two

binding sites per tetramer. This dimer-dimer interface, comprising the two T₄ binding sites, is the weaker dimer-dimer interface and is the one that comes apart first in the process of tetramer dissociation.

Role in disease

TTR misfolding and aggregation is known to be associated with

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

diseases including wild-type transthyretin amyloidosis, hereditary transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC). TTR tetramer dissociation is known to be rate-limiting for amyloid fibril formation. However, the monomer also must partially denature in order for TTR to be mis-assembly competent, leading to a variety of aggregate structures, including

fibrils. At least 114 disease-causing mutations in this gene have been discovered. While wild type TTR can dissociate, misfold, and aggregate, leading to SSA (senile systemic amyloidosis),

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

s within TTR are known to destabilize the tetramer composed of mutant and wild-type TTR subunits, facilitating more facile dissociation and/or misfolding and amyloidogenesis. A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly associated with 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 more benign. Deposition of TTR amyloid is generally observed extracellularly, although TTR deposits are also clearly observed within the cardiomyocytes of the heart. Treatment of familial (hereditary) TTR amyloid disease has historically relied on

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

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 reduce the mutant TTR levels in the body to < 5% of pretransplant levels. Certain mutations, however, cause CNS amyloidosis, and due to their production by the choroid plexus, the CNS TTR amyloid diseases do not respond to gene therapy mediated by liver transplantation. In 2011, the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

approved tafamidis (Vyndaqel) for the amelioration of FAP. Tafamidis kinetically stabilizes the TTR tetramer, preventing tetramer dissociation required for TTR amyloidogenesis and degradation of the autonomic nervous system and/or the peripheral nervous system and/or the heart. TTR is also thought to have beneficial side effects, by 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 Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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. There is now strong genetic and pharmacologic data (see

website for the tafamidis clinical trial results) indicating that the process of amyloid fibril formation leads to the degeneration of post-mitotic tissue causing FAP and likely FAC and SSA. Evidence points to the oligomers generated in the process of amyloidogenicity leading to the observed proteotoxicity. Transthyretin level in cerebrospinal fluid has also been found to be lower in patients with some neurobiological disorders such as

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. The reduced level of transthyretin in the CSF may indicate a lower thyroxine transport in brains of patients with schizophrenia. Transthyretin is known to contain a Gla domain, and thus be dependent for production on post-translational modification requiring

vitamin K Vitamin K is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-translational modification, post-synthesis modification of certain proteins ...

, but the potential link between vitamin k status and thyroid function has not been explored. Because transthyretin is made in part by the

, it can be used as an immunohistochemical marker for choroid plexus papillomas as well as carcinomas. As of March 2015, there are two ongoing clinical trials undergoing recruitment in the United States and worldwide to evaluate potential treatments for TTR amyloidosis.

Interactions

Transthyretin has been shown to interact with perlecan.

References

External links