Article: Transthyretin

Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4). It functions in concert with two other proteins, thyroxine-binding globulin (TBG) and albumin in a system where TBG possesses the highest affinity, yet lowest plasma concentration, TTR has a lower affinity, yet higher concentration, and albumin is the poorest binder, but has a much higher plasma concentration. TTR also acts as a carrier of retinol (vitamin A) through an association with retinol binding protein (RBP). TTR is known to be associated with the amyloid diseases senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC). TTR was originally called prealbumin because it ran faster than albumin on electrophoresis gels.

TTR is a 55 kDa homotetramer with a dimer of dimers configuration. Each monomer is a 127 residue polypeptide rich in beta sheet structure. Association of two monomers forms an extended beta sandwich. Further association of another identical set of monomers produces the homotetrameric structure. The two thyroxine binding sites per tetramer sit at the interface between the latter set of dimers.

View of TTR crystal structure

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 many aromatic 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.

Role in disease

TTR is able to deposit as amyloid fibrils, causing neurodegeneration and organ failure. Both point mutations 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 the blood brain barrier, do not respond to this therapy.

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.