Transthyretin

Last updated
TTR
Transthyretin.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TTR , CTS, CTS1, HEL111, HsT2651, PALB, TBPA, transthyretin, ATTN
External IDs OMIM: 176300 MGI: 98865 HomoloGene: 317 GeneCards: TTR
Orthologs
SpeciesHumanMouse
Entrez

7276

22139

Ensembl

ENSG00000118271

ENSMUSG00000061808

UniProt

P02766

P07309

RefSeq (mRNA)

NM_000371

NM_013697

RefSeq (protein)

NP_000362

NP_038725

Location (UCSC) Chr 18: 31.56 – 31.6 Mb Chr 18: 20.8 – 20.81 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol 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 secretes TTR into the cerebrospinal fluid.

TTR was originally called prealbumin [5] (or thyroxine-binding prealbumin) because it migrated faster than albumin 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.

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:

ProteinBinding strengthPlasma concentration
thyroxine-binding globulin (TBG)highestlowest
transthyretin (TTR or TBPA)lowerhigher
albumin poorestmuch higher

In cerebrospinal fluid TTR is the primary carrier of T4. 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, [6] diflunisal, [7] [8] [9] and flufenamic acid), [10] and toxicants (PCB [11] ).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127-residue polypeptide rich in beta sheet 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. [12]

Role in disease

TTR misfolding and aggregation is known to be associated with amyloid diseases [13] including wild-type transthyretin amyloidosis, [14] hereditary transthyretin amyloidosis, [15] familial amyloid polyneuropathy (FAP), [16] [17] and familial amyloid cardiomyopathy (FAC). [18]

TTR tetramer dissociation is known to be rate-limiting for amyloid fibril formation. [19] [20] [21] However, the monomer also must partially denature in order for TTR to be mis-assembly competent, leading to a variety of aggregate structures, including amyloid fibrils. [22]

At least 114 disease-causing mutations in this gene have been discovered. [23] While wild type TTR can dissociate, misfold, and aggregate, leading to SSA (senile systemic amyloidosis), point mutations 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. [24] A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly associated with FAP. [25] 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. [18] SSA is estimated to affect over 25% of the population over age 80. [14] 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 as a crude form of gene therapy. [26] 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 approved tafamidis (Vyndaqel) for the amelioration of FAP. [6] Tafamidis kinetically stabilizes the TTR tetramer, preventing tetramer dissociation required for TTR amyloidogenesis and degradation of the autonomic nervous system [27] and/or the peripheral nervous system and/or the heart. [21]

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. 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. [28]

There is now strong genetic [29] [30] and pharmacologic data (see European Medicines Agency 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. [31] [32]

Transthyretin level in cerebrospinal fluid has also been found to be lower in patients with some neurobiological disorders such as schizophrenia. [33] 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, but the potential link between vitamin k status and thyroid function has not been explored.

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

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. [34] [ needs update ]

Interactions

Transthyretin has been shown to interact with perlecan. [35]

Related Research Articles

<span class="mw-page-title-main">Amyloid</span> Insoluble protein aggregate with a fibrillar morphology

Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.

<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta 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-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Diflunisal</span> NSAID analgesic and anti-inflammatory drug

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, 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 widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

<span class="mw-page-title-main">Familial amyloid polyneuropathy</span> Medical condition

Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR, or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied. FAP can be ameliorated by liver transplantation.

<span class="mw-page-title-main">Cardiac amyloidosis</span> Medical condition

Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with a corrected analysis only during autopsy. Advancements of technologies have increased earlier accuracy of diagnosis. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.

<span class="mw-page-title-main">Alpha sheet</span> Secondary protein structure

Alpha sheet is an atypical secondary structure in proteins, first proposed by Linus Pauling and Robert Corey in 1951. The hydrogen bonding pattern in an alpha sheet is similar to that of a beta sheet, but the orientation of the carbonyl and amino groups in the peptide bond units is distinctive; in a single strand, all the carbonyl groups are oriented in the same direction on one side of the pleat, and all the amino groups are oriented in the same direction on the opposite side of the sheet. Thus the alpha sheet accumulates an inherent separation of electrostatic charge, with one edge of the sheet exposing negatively charged carbonyl groups and the opposite edge exposing positively charged amino groups. Unlike the alpha helix and beta sheet, the alpha sheet configuration does not require all component amino acid residues to lie within a single region of dihedral angles; instead, the alpha sheet contains residues of alternating dihedrals in the traditional right-handed (αR) and left-handed (αL) helical regions of Ramachandran space. Although the alpha sheet is only rarely observed in natural protein structures, it has been speculated to play a role in amyloid disease and it was found to be a stable form for amyloidogenic proteins in molecular dynamics simulations. Alpha sheets have also been observed in X-ray crystallography structures of designed peptides.

<span class="mw-page-title-main">Proteinopathy</span> Medical condition

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.

Jeffery W. Kelly is an American businessman and chemist who is on the faculty of the Scripps Research Institute in La Jolla, California.

The familial amyloid neuropathies are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

<span class="mw-page-title-main">Tafamidis</span> Medication for transthyretin amyloidosis

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 cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.

Amyloid cardiomyopathy is a condition resulting in the death of part of the myocardium. It is associated with the systemic production and release of many amyloidogenic proteins, especially immunoglobulin light chain or transthyretin (TTR). It can be characterized by the extracellular deposition of amyloids, foldable proteins that stick together to build fibrils in the heart. The amyloid can be seen under polarized light in congo red stained biopsy.

<span class="mw-page-title-main">Familial Amyloidosis, Finnish Type</span> Medical condition

Familial Amyloidosis, Finnish Type (FAF), also called hereditary gelsolin amyloidosis and AGel amyloidosis (AGel), is an amyloid condition with a number of associated cutaneous and neurological presentations deriving from the aberrant proteolysis of a mutated form of plasma gelsolin. First described in 1969 by the Finnish ophthalmologist Jouko Meretoja, FAF is uncommon with 400–600 cases described in Finland and 15 elsewhere.

Familial amyloid cardiomyopathy (FAC), or transthyretin amyloid cardiomyopathy (ATTR-CM) results from the aggregation and deposition of mutant and wild-type transthyretin (TTR) protein in the heart. TTR is usually circulated as a homo-tetramer—a protein made up of four identical subunits—however, in FAC populations, TTR dissociates from this typical form and misassembles into amyloid fibrils which are insoluble and resistant to degradation. Due to this resistance to degradation, when amyloid fibrils accumulate in the heart's walls, specifically the left ventricle, rigidity prevents the heart from properly relaxing and refilling with blood: this is called diastolic dysfunction which can ultimately lead to heart failure.

Alnylam Pharmaceuticals, Inc. is an American biopharmaceutical company focused on the discovery, development and commercialization of RNA interference (RNAi) therapeutics for genetically defined diseases. The company was founded in 2002 and is headquartered in Cambridge, Massachusetts. In 2016, Forbes included the company on its "100 Most Innovative Growth Companies" list.

Chemical chaperones are a class of small molecules that function to enhance the folding and/or stability of proteins. Chemical chaperones are a broad and diverse group of molecules, and they can influence protein stability and polypeptide organization through a variety of mechanisms. Chemical chaperones are used for a range of applications, from production of recombinant proteins to treatment of protein misfolding in vivo.

Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA), is a disease that typically affects the heart and tendons of elderly people. It is caused by the accumulation of a wild-type protein called transthyretin. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated transthyretin protein tends to deposit much earlier than in WTTA due to abnormal conformation and bioprocessing. It belongs to a group of diseases called amyloidosis, chronic progressive conditions linked to abnormal deposition of normal or abnormal proteins, because these proteins are misshapen and cannot be properly degraded and eliminated by the cell metabolism.

Hilal Lashuel is an American-Yemeni neuroscientist and chemist, currently an associate professor at the EPFL. His research focuses on protein misfolding and aggregation in the pathogenesis of Alzheimer's and Parkinson's diseases.

Vutrisiran, previously known as (ALN-TTRSC02), sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double stranded small interfering RNA (siRNA) that interferes with the expression of the transthyretin (TTR) gene. Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine. Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart. Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.

Eplontersen, sold under the brand name Wainua, is a medication used for the treatment of transthyretin-mediated amyloidosis. It is a transthyretin-directed antisense oligonucleotide. It was developed to treat hereditary transthyretin amyloidosis by Ionis Pharmaceuticals and AstraZeneca.

References

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  34. ↑ Clinical trial number NCT01960348 for "APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis" at ClinicalTrials.gov
  35. ↑ Smeland S, Kolset SO, Lyon M, Norum KR, Blomhoff R (September 1997). "Binding of perlecan to transthyretin in vitro". Biochem. J. 326 (3): 829–36. doi:10.1042/bj3260829. PMC   1218739 . PMID   9307034.

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