Transthyretin (TTR or TBPA) is a

transport protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

in the plasma and

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

that transports the thyroid hormone thyroxine (T₄) and

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xeroph ...

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 nerv ...

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 the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Album ...

electrophoresis Electrophoresis, from Ancient Greek ἤλεκτρον (ḗlektron, "amber") and φόρησις (phórēsis, "the act of bearing"), is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric fi ...

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. Transthyretin protein is encoded by the ''TTR'' gene located on the 18th chromosome.

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 Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies. ...

(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, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sourc ...

), drugs (

Tafamidis Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyo ...

, or Vyndaqel, diflunisal, 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 organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

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. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

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 ge ...

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 thyroxine 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 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the huma ...

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—consequence ...

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 Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...

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 medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

approved

or Vyndaqel for the amelioration of FAP. Vyndaqel 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 Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...

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 that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. 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 by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. 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 Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins wi ...

, and thus be dependent for production on post-translational modification requiring

vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...

, 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 Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with

Perlecan Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the ''HSPG2'' gene. The HSPG2 gene codes for a 4,391 am ...

References

External links