Transthyretin structure

Figure 14.8 Proposed model of p sheet helix of the fibrous form of transthyretin. The repeating unit of the P helix comprises 24 P strands with an average twist of 15° between each strand giving a complete turn of 360°. Four transthyretin polypeptide chains contribute to the repeat unit and are shown here in different colors. (Adapted from C. Blake and L. Serpell, Structure 4 989-998, 1996.)...

Blake, C., Serpell, L. Synchrotron x-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous P sheet helix. Structure 4 989-998, 1996. 

Lans, M.C., Klasson-Wehler, E., and Willemsen, M. et al. (1993). Structure-dependant competitive interaction of hydroxy-PCB, PCDD, and PCDE with transthyretin. Chemico-Biological Interactions 88, 7-21. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Kelly JW, Colon W, Lai Z, Lashuel HA, McCulloch J, McCutchen SL, Miroy GJ, Peterson SA. Transthyretin quaternary and tertiary structural... 

The molecular structure of the amyloid fibrils formed by fragment 105-115 of transthyretin (TTR10sns, YTIAALLSPTS) has been characterized by solid-state NMR. The fibril backbone structure was first established based on the TALOS analysis of the 15N and 13C chemical shifts [89]. Using the correlation experiments of Hn(0-N(0—CV-H0 , Ha(0-Ca(0-N(i.+1)-HN(i+1), and N -Tco-N, a total of 41 constraints on 19 backbone torsion angles have been obtained in a... 

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

Transthyretin is a 147-residue transporter protein that is deposited as amyloid in senile systemic amyloidosis and familial amyloid polyneuropathy (Benson and Uemichi, 1996 Saraiva, 1995 Westermark et al., 1990). The protein s native structure is a 55-kDa dimer of dimers, or homotetramer, composed mainly of /1-sheets (Blake et al., 1978). The native monomer-to-monomer interface is formed by mutual, antiparallel extension of each monomer s two sheets (Fig. 7A) both four-stranded sheets in the monomers (DAGH and GBEF) become eight-stranded sheets in the dimer (DAGHH G A D and CBEFF E B C ) (Blake et al, 1978). In vitro at low... 

Lans MC, Klasson-Wehler E, Willemsen M, et al. 1993. Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin. Chem Biol Interactions 88 7-21. 

In another report, a microchip was interfaced to MS for the detection of the tetrameric plasma protein (transthyretin) which was involved in the transport of thyroxine. Screening of small molecules, including the natural ligand, thyroxine, that could stabilize the tetramer structure was carried out [779]. 

A. Wojtczak et al., Structure of rat transthyretin (rTTR) complex with thyroxine at 2.5 A resolution First non-biased insight into thyroxine binding reveals different hormone orientation in two binding sites. Acta. Cryst. D 57, 1061-1070 (2001)... 

Structural perturbation or conformational change in the soluble protein is important for amyloid formation. The observation of an amyloidogenic intermediate of transthyretin (TTR) in acidic pH led to the hypothesis of conformational perturbation as a prerequisite for amyloid fibril formation [6]. 

Transthyretin amyloidosis (also called familial amyloid polyneuropathy) is an autosomal dominant syndrome characterized by peripheral neuropathy. This disease results from one of five mutations identified thus far in the gene for transthyretin. Transthyretin is also called prealbumin (although it has no structural relationship to albumin) because it migrates ahead of albumin in standard electrophoresis at pH 8.6. Transthyretin is synthesized in the liver and is a normal plasma protein with a concentration of 20-40 mg/dL. It transports thyroxine and retinol binding protein (Chapter 38). The concentration of transthyretin is significantly decreased in malnutrition and plasma levels are diagnostic of disorders of malnutrition (Chapter 17). 

The gene for transthyretin resides on chromosome 18 and it is expressed in a constitutive manner. The primary structure of transthyretin consists of 127 amino acid residues and eight /1-sheet structures arranged in an antiparallel conformation on parallel planes (Figure 4-15). 

The structure of transthyretin. The molecule contains eight antiparallel A-strands (A-H) arranged in two parallel planes. The circulating form of transthyretin is a tetramer. Some mutations in the transthyretin gene are associated with amyloidosis and eight of the amino acid alterations causing this disease are indicated. In plasma, transthyretin is a tetramer composed of identical monomers. It appears that mutations cause the monomeric unfolded intermediate of transthyretin to aggregate into an insoluble A-amyloid fibril formation. 

Fig. 13. Structures of polypeptides determined by MAS solid-state NMR. The PDB file numbers are shown where available, (a) The dipeptide glycyl isoleucine, (b) The tripeptide iV-formyl-L-Met-L-Eeu-L-Phe-OH. (c) The a-spectrin SH3 domain, (d) An 11-amino acid stretch of transthyretin...

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