- Transthyretin
Transthyretin (TTR) is a serum and
cerebrospinal fluid carrier of thethyroid hormone thyroxine (T4).TTR was originally called "prealbumin" [MeshName|Prealbumin] because it ran faster than
albumins onelectrophoresis gels.Binding affinities
It functions in concert with two other thyroid hormone binding proteins in the serum:
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 withretinol 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 manyaromatic compounds , and generally does not bind T4 in serum, there is speculation that TTR's "true function" is to generally sweep up toxic and foreign compounds in the blood stream.tructure
TTR is a 55 kDa homotetramer with a dimer of dimers configuration that is synthesized in the
liver ,choroid plexus andretinal pigment epithelium . Each monomer is a 127 residuepolypeptide rich inbeta sheet structure. Association of two monomers forms an extended beta sandwich. Further association of another identical set of monomers produces the homotetrameric structure. The twothyroxine 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. Bothpoint mutation s 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 effect 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 theblood 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.
Wikimedia Foundation. 2010.
