Extremely stable towards denaturation, it is a homotetramer with 4 peptide chains of 13.75 Kda approx.. It has by now been very extensively studied and a useful summary can be found on Wikipedia. Today there are a remarkable 361 3D transthyretin structures from various species published in the Protein data bank (PDB). When I started my D.Phil. research a low resolution structure (6 Å ) balsa wood model was available (figure left), but it was impossible to determine the location of the protein subunits The first atomic level structure determination was published in my 1973 Oxford D.Phil thesis and later refined at higher resolution (1).
A physical model was then built up using accurately sized wire models (from Cambridge Repetition Engineers) of the amino acids superimposed by reflection within the electron density sheets. An heroic enterprise compared with the sophisticated computer molecular modelling of today. The first structure determination was published in my 1973 Oxford D.Phil thesis (1) and later refined at higher resolution (2).
Transthyretin was the second plasma protein 3D structure to be solved (the first was IgG). The stability of transthyretin was immediately clear from the high resolution model. Monomers in the tetrameric structure formed two pairs of continuous ß-pleated sheets and denaturation of the tetramer would probably lead to extensive aggregation.
The ß-pleated sheet structure was fairly novel at the time, but had been observed in some other 3D structures: Concanavalin A and IgG. Up until then, most proteins were assumed to contain large regions of alpha helix. In the view on the left, the large water filled channel between opposing dimers was the obvious place for thyroxine and other ligand binding.
A much later finding relates to the amyloidogenic property of human transthyretin (TTR) when single point mutations (most commonly valine to methionine) leads to the aggregation of the molecule. Truncation of the N - terminal region of the protein chain seems to prevent native tetramer formation leading to the observed amyloid fibrils. Neuropathy is often a major manifestation of systemic amyloidosis. It is most frequently seen in patients with hereditary transthyretin amyloidosis, but is also present in 20% of patients with systemic immunoglobulin light chain (primary) amyloidosis. Familial amyloid polyneuropathy (FAP) is the most common form of inherited amyloidotic polyneuropathy, with clinical and electrophysiologic findings similar to neuropathies with differing etiologies (e.g., diabetes mellitus). Hereditary amyloidosis is an adult-onset autosomal-dominant disease with varying degrees of penetrance.
It is caused by specific gene mutations, but demonstration that a patient has one such mutation does not confirm the diagnosis of amyloidosis. Diagnosis requires tissue biopsy with demonstration of amyloid deposits either by special histochemical stains or electron microscopy. Transthyretin amyloidosis is treated by liver transplantation, which eliminates the mutated transthyretin from the blood, but for some patients continued amyloid deposition can occur from wild-type (normal) transthyretin [Abstracted from: Merrill D Benson 1, John C Kincaid (2007)] Muscle Nerve 36(4): 411-23
Recent years(2) have seen drugs which interfere with the deposition of misfolded TTR at various stages of the cascade underlying TTR amyloidosis progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin-3-gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid).
- Structure of prealbumin at 2.5 Å. Blake, C.C.F., Geisow, M.J., Swan, I.D.A., Rerat, C. & Rerat, B.(1974) J Mol Biol 88: 1-12
- Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. Blake, C.C., Geisow, M.J., Oatley, S.J., Rerat, B., Rerat, C.(1978) J Mol Biol 121: 339-356.
- Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy? Maximilian L. Müller,Javed Butler,Bettina Heidecker (2020) European Journal of Heart Failure 22: 39-53