Transthyretin
Encyclopedia
Transthyretin is a serum
and cerebrospinal fluid
carrier of the thyroid hormone thyroxine
(T4) and retinol binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid
.
TTR was originally called prealbumin because it ran faster than albumin
on electrophoresis
gels.
In cerebrospinal fluid TTR is the primary carrier of T4, as albumin is not present.
TTR also acts as a carrier of retinol
(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
), drugs (Tafamidis, or Vyndaqel, diflunisal
flufenamic acid
, and toxins (PCB
). Since TTR binds promiscuously to many aromatic compounds, there is speculation that TTR's "true function" is to sweep up toxic and foreign compounds in the bloodstream.
, choroid plexus
and retinal pigment epithelium for secretion into the eye. Each monomer is a 127-residue polypeptide rich in beta sheet
structure. Association of two monomers forms an extended beta sandwich. Further association of two of these dimers 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 the comes apart first in the process of tetramer dissociation.
diseases senile systemic amyloidosis (SSA), 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 to be mis-assembly competent, leading to a variety of aggregate structures including amyloid
fibrils. While wild type TTR can dissociate, misfold and aggregate leading to SSA, point mutation
s within TTR are known to destabilize the tetramer 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 TTR amyloid disease has historically relied on 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 reduce the mutant TTR levels in the body to < 5% of pretransplant levels. Certain mutations, however, cause CNS amyloidosis, and due to the 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
approved Tafamidis or Vyndaqel for the amelioration of FAP. Vyndaqel kinetically stabilizes the TTR tetramer preventing tetramer dissociation required for TTR amyloidogenesis and degradation of the autnomic nervous system and/or the peripheral nervous system and/or the heart.
TTR is also thought to have beneficial side, 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
. 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 geneticand pharmacologic data (the Tafamidis 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
. 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.
. 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. 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.
with Perlecan
.
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
carrier of the thyroid hormone thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(T4) and retinol binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
.
TTR was originally called prealbumin because it ran faster than albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
on electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
gels.
Binding affinities
It functions in concert with two other thyroid hormone-binding proteins in the serum:| Protein | Binding strength | Plasma concentration |
|---|---|---|
| thyroxine-binding globulin Thyroxine-binding globulin Thyroxine-binding globulin binds thyroid hormone in circulation. It is one of three proteins responsible for carrying the thyroid hormones thyroxine and 3,5,3’-triiodothyronine in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3, but is present in the lowest... (TBG) |
highest | lowest |
| transthyretin (TTR) | lower | higher |
| albumins | poorest | much higher |
In cerebrospinal fluid TTR is the primary carrier of T4, as albumin is not present.
TTR also acts as a carrier of retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
(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
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
), drugs (Tafamidis, or Vyndaqel, diflunisal
Diflunisal
Diflunisal is a non-steroidal anti-inflammatory drug . It was developed by Merck Sharp & Dohme in 1971 after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now...
flufenamic acid
Flufenamic acid
Flufenamic acid, also known as Fluffy or Fluf, is a non-steroidal anti-inflammatory drug. It is pale yellow crystalline powder....
, and toxins (PCB
Polychlorinated biphenyl
Polychlorinated biphenyls are a class of organic compounds with 2 to 10 chlorine atoms attached to biphenyl, which is a molecule composed of two benzene rings. The chemical formula for PCBs is C12H10-xClx...
). Since TTR binds promiscuously to many aromatic compounds, 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 liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, choroid plexus
Choroid plexus
The choroid plexus is a structure in the ventricles of the brain where cerebrospinal fluid is produced...
and retinal pigment epithelium for secretion into the eye. Each monomer is a 127-residue polypeptide rich in beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
structure. Association of two monomers forms an extended beta sandwich. Further association of two of these dimers produces the homotetrameric structure and creates the two thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
binding sites per tetramer. This dimer-dimer interface comprising the two T4 binding sites is the weaker dimer-dimer interface and is the one the comes apart first in the process of tetramer dissociation.
Role in disease
TTR is known to be associated with the amyloidAmyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
diseases senile systemic amyloidosis (SSA), familial amyloid polyneuropathy
Familial amyloid polyneuropathy
Familial amyloid polyneuropathy , also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of paramyloidosis, and was first identified and described by Portuguese neurologist...
(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 to be mis-assembly competent, leading to a variety of aggregate structures including amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
fibrils. While wild type TTR can dissociate, misfold and aggregate leading to SSA, point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
s within TTR are known to destabilize the tetramer 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 TTR amyloid disease has historically relied on liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
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 the 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
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
approved Tafamidis or Vyndaqel for the amelioration of FAP. Vyndaqel kinetically stabilizes the TTR tetramer preventing tetramer dissociation required for TTR amyloidogenesis and degradation of the autnomic nervous system and/or the peripheral nervous system and/or the heart.
TTR is also thought to have beneficial side, 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
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. 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 geneticand pharmacologic data (the Tafamidis 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
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. 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
Choroid plexus
The choroid plexus is a structure in the ventricles of the brain where cerebrospinal fluid is produced...
, it can be used as an immunohistochemical marker for choroid plexus papillomas.
Nutritional Assessment
In medicine, nutritional status can be assessed by measuring concentrations of transthyretin in the bloodBlood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
. In theory, other transport proteins such as albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
or transferrin
Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...
could be used but transthyretin is preferred because of its shorter half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
, although this means that its concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
more closely reflects recent dietary intake rather than overall nutritional status. Transthyretin concentration has been shown to be a good indicator of whether or not a malnourished patient will develop refeeding syndrome
Refeeding syndrome
Refeeding syndrome is a syndrome consisting of metabolic disturbances that occur as a result of reinstitution of nutrition to patients who are starved or severely malnourished. Renourishment is the process of avoiding refeeding syndrome...
upon commencement of refeeding, via either the enteral
Enteral
In pharmacology, Enteral is a term used to describe routes of drug administration that involve absorption of the drug through the gastrointestinal tract. The term may also be used to describe something as residing in the gastrointestinal tract...
, parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
or oral
Mouth
The mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....
routes.
| 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Perlecan
Perlecan
Perlecan also known as basement membrane-specific heparan sulfate proteoglycan core protein or heparan sulfate proteoglycan 2 , is a protein that in humans is encoded by the HSPG2 gene....
.