Transthyretin protein

The other major class of extracellular LBPs of mammals is the lipocalins (Flower, 1996). These are approximately 20 kDa, P-sheet-rich proteins, performing functions such as the transport of retinol in plasma or milk, the capture of odorants in olfaction, invertebrate coloration, dispersal of pheromones, and solubilizing the lipids in tears (Flower, 1996). The retinol-binding protein (RBP) of human plasma is found in association with a larger protein, transthyretin, the complex being larger than the kidney threshold and thus not excreted, although the RBP itself may dissociate from the complex to interact with cell surface receptors in the delivery of retinol (Papiz et al., 1986 Sundaram et al., 1998). 

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]. 

Familial transthyretin amyloidosis (ATTR) is a hereditary degenerative disease which is closely associated with single amino acid substitutions in the plasma protein transthyretin (TTR), a 127 amino acid protein (Mr 13,761 Da) that is tetrameric in its native state.28 The clinical manifestations of ATTR are related to specific mutations of TTR (e.g., Val30 - Met and Thr60 — Ala). The definitive diagnosis is often established on the basis of the... 

Liver Storage and Release of Retinol Tissues can take up retinyl esters from chylomicrons, but most is left in the chylomicron remnants that are taken up into the liver by endocytosis. The retinyl esters are hydrolyzed at the hepatocyte cell membrane, and free retinol is transferred to the rough endoplasmic reticulum, where it binds to apo-RBP. Holo-RBP then migrates through the smooth endoplasmic reticulum to the Golgi and is secreted as a 1 1 complex with the thyroid hormone binding protein, transthyretin (Section 2.2.3). 

Chu et al. [81,82] observed changes in the thyroid when rats were administered PCDEs. Rosiak et al. [104] have lately reported that some PCDEs can cause hypothyroidism in rats. PCDEs 71 and 102, which have closest resemblance to thyroxine (T4), were shown to cause hypothyroidism in pregnant rats and PCDEs 71,102, and 153 in juvenile rats exposed in utero. PCDEs 71 and 102 have been fetotoxic in mice [92]. Rosiak et al. [104] suggested that, e.g., the inhibition of the release of T4 from thyroid follicular cells by PCDEs or binding of PCDEs to thyroid hormone binding protein, transthyretin, could decrease T4 levels. Triiodothyronine (T3) levels were not altered by PCDEs 71,102, and 153. 

Thyroid hormones have a lengthy life-span in the bloodstream — several days — probably because they are bound to proteins in the circulation. More than of T4 and T3 is bound to plasma proteins. These prolerns arc thyroid hormone-binding protein, transthyretin, and albumin. Most of the hormone is carded by thyroid hormone-binding protein. Transthyretin (from thyroid and retinol) occurs in a Irl complex with retinol-binding protein In the bloodstream. This complex serves to prevent the loss of retinol-binding protein, which is a small protein, in the urine. Transthyretin has also been called prealbumin, it binds T4 and not TJ,... 

Vitamin A homeostasis was altered in rats that were exposed to 100 mg/kg/day (only tested dose) of PCB 169 in the diet for 77 days (Bank et al. 1989). Effects included significantly decreased hepatic vitamin A, increased renal vitamin A, increased serum retinol, decreased plasma clearance and half-time of injected retinol (i.e., intravenously administered [ Hjretinol-labeled retinol binding protein-transthyretin complex), decreased hepatic and increased renal uptake uptake of injected retinol, and increased urinary and fecal excretion of injected retinol. 

A possible explanation for the highly selective retention of the OH-PCBs in blood may be their structural resemblance with thyroxin. Both rats and mice metabolize PCB 77 by CYPIA to the 1,2-shift metabolite, 4-OH-3,5,3, 4 -PCB, 5-OH 3,3, 4,4 -PCB, and 6-OH-3,3, 4,4 -PCB (McKinley et al. 1993 Morse et al. 1995). Only the 4-OH metabolite was selectively retained, with blood containing 4-OH-3,5,3, 4 -PCB at a concentration 15 times higher than the parent compound, 5 days after oral exposure to PCB 77 in mice (Bergman et al. 1994). This metabolite was found to be bound to a thyroxin-transporting protein (transthyretin) in the blood (Brouwer et al. 1986). Competitive binding studies of OH-PCBs relative to T4 and computer modeling showed that OH-PCBs with the substituents in meta or para positions were much more effective competitors for T4 than if the substituents were bound in an ortho position (Rickenbacher et al. 1986). 

In typical applications, fluorescence anisotropy has been used to study the effect of the amyloidogenic protein transthyretin on the fluidity of the plasma membrane of neuroblastoma cells [182] and changes in the mobility of various domains of a neurotoxin when the protein binds to the acetylcholine receptor [183]. 

Tetrabromobisphenol A (4,4 -isopropylidenebis(2,6-dibromophenol) TBBPA) is the most widely used BFR in terms of production quantities [2]. It is used as both a reactive and an additive BFR in a variety of polymers, epoxy resins, and adhesives and, in particular, is a constituent in printed circuit boards at levels up to 34% (mass fraction). The acute toxicity of TBBPA is relatively low however, concern for its potential as an endocrine disrupter exists. TBBPA shares structural similarities to thyroxine (T4), and the compoimd competitively binds to the thyroid hormone transport protein transthyretin [135]. Analysis by gas chromatography requires derivitization, and LC methods are preferred to reduce sample processing. Biotransformation of TBBPA... 

Mata, N. L. Phan, K. Han, Y. Assay of retinol-binding protein-transthyretin interaction and techniques to identify competing ligands. Methods Mol. Biol. 2010,652,209-227. 

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