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The FEBS Journal Nov 2023Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small...
Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone-related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone-related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid-disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors.
Topics: Animals; Humans; Female; Pregnancy; Prealbumin; Rafoxanide; Placenta; Thyroid Hormones; Amyloidosis; Anthelmintics; Anti-Infective Agents
PubMed: 37522420
DOI: 10.1111/febs.16915 -
Scandinavian Journal of Immunology 1980The major component, protein ASC, isolated from the amyloid fibrils in senile cardiac amyloidosis, was characterized by structural studies of some peptic peptides. One...
The major component, protein ASC, isolated from the amyloid fibrils in senile cardiac amyloidosis, was characterized by structural studies of some peptic peptides. One of the peptides has an amino acid sequence identical to residues 70-90 in human prealbumin, and three other smaller peptides have a primary structure identical to that in positions 96-107, 109-115 and 121-127. The amino acid composition of the protein resembles that of human prealbumin but shows some characteristic differences. The protein has a blocked N-terminus and gives no visible precipitin reaction with antiserum to human prealbumin.
Topics: Aged; Amino Acid Sequence; Amino Acids; Amyloid; Amyloidosis; Cross Reactions; Humans; Peptides; Prealbumin
PubMed: 7244554
DOI: 10.1111/j.1365-3083.1980.tb00098.x -
IUBMB Life Jun 2010Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial... (Review)
Review
Transthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T(4)) and retinol. Mutated TTR leads to familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR amyloid deposition particularly in peripheral nerves. Beside its transport activities, TTR is a cryptic protease and participates in the biology of the nervous system. Several studies have been directed at finding new ligands of TTR to further explore the biology of the protein. From the identified ligands, some were in fact TTR protease substrates. In this review, we will discuss the existent information concerning TTR ligands/substrates.
Topics: Amyloid Neuropathies, Familial; Humans; Ligands; Mutation; Prealbumin
PubMed: 20503435
DOI: 10.1002/iub.340 -
The Journal of Histochemistry and... May 1983Cerebrospinal fluid (CSF) is generally considered to be derived from plasma through a combined process of ultrafiltration and secretion by the choroid plexus. However,...
Cerebrospinal fluid (CSF) is generally considered to be derived from plasma through a combined process of ultrafiltration and secretion by the choroid plexus. However, the mechanisms ultimately responsible for achieving the final protein composition of CSF are uncertain. Some proteins, in particular prealbumin, are present in quantities not easily explained by usual physicochemical considerations. To investigate the possibility of de novo synthesis by choroid epithelium, we have examined human choroid plexus an ependyma for the presence of prealbumin. Using the peroxidase-antiperoxidase method at the light and electron microscopic level, as well as immunofluorescence, we localized prealbumin in choroid epithelial cytoplasm on the endoplasmic reticulum and in association with the Golgi apparatus. Ependymal cells and stroma did not reveal immunocytochemical labeling. These findings indicate that the choroid plexus epithelium contributes to the final CSF composition by de novo protein synthesis.
Topics: Animals; Choroid Plexus; Epithelium; Histocytochemistry; Humans; Immunoenzyme Techniques; Microscopy, Electron; Microscopy, Fluorescence; Prealbumin; Rabbits; Serum Albumin
PubMed: 6341455
DOI: 10.1177/31.5.6341455 -
Clinica Chimica Acta; International... Oct 1983Prealbumin (PA) was purified 35-fold from human serum and antibodies raised against it in rabbits. A 2-hour radioimmunoassay (RIA) using polyethyleneglycol (PEG) to...
Prealbumin (PA) was purified 35-fold from human serum and antibodies raised against it in rabbits. A 2-hour radioimmunoassay (RIA) using polyethyleneglycol (PEG) to separate bound and free PA was used to determine levels in body fluids. Using patient serum specimens the new method was compared with an electroimmunoassay (EIA) method and the regression equation obtained was: y = 1.13x - 9.91. The RIA and EIA methods compared favourably with respect to precision to practicability and economy. The RIA method seems especially suitable for large scale assays of PA and is 100 times more sensitive than EIA. Preliminary estimations of PA with the RIA method in plasma, cerebrospinal fluids, amniotic fluids, duodenal juices and urines were carried out. The results indicate that this method can be conveniently used to assay PA in body fluids where the protein is present in low concentration.
Topics: Amniotic Fluid; Body Fluids; Duodenum; Female; Humans; Immunoenzyme Techniques; Prealbumin; Pregnancy; Radioimmunoassay
PubMed: 6360427
DOI: 10.1016/0009-8981(83)90185-7 -
Proceedings of the National Academy of... Feb 1984Prealbumin from an individual with heredofamilial amyloid polyneuropathy of Swedish origin was isolated from plasma by using a three-step procedure involving ion... (Comparative Study)
Comparative Study
Prealbumin from an individual with heredofamilial amyloid polyneuropathy of Swedish origin was isolated from plasma by using a three-step procedure involving ion exchange, Affi-gel Blue affinity chromatography, and gel filtration. This prealbumin and its associated amyloid fibril subunit protein were digested with trypsin and the resulting peptides were separated by high performance liquid chromatography. Comparison with normal prealbumin peptides showed that an amino acid substitution of a methionine for a valine had occurred at position 30. In the plasma prealbumin, the abnormal residue accounted for 1/3rd of the material while in the amyloid fibrils it accounted for 2/3rds. From this sequence information and the known three-dimensional structure of the prealbumin molecule, a mechanism for the amyloid formation is proposed. It involves formation of the amyloid fibrils by addition of prealbumin dimers or tetramers to the aggregate. Each dimer must contain at least one variant peptide chain while the tetramer must contain at least two abnormal chains. Either of these models can account for the observed amount of normal prealbumin in amyloid fibrils. No proteolytic processing of this molecule is required because the entire undegraded prealbumin molecule is found in the fibrils.
Topics: Amino Acid Sequence; Amyloid; Humans; Nervous System Diseases; Peptide Fragments; Prealbumin; Protein Precursors; Reference Values; Trypsin
PubMed: 6583672
DOI: 10.1073/pnas.81.3.694 -
Biochimica Et Biophysica Acta Oct 2000Transthyretin (TTR, formerly called prealbumin), one of the transporters of the hormone thyroxine and the lipocalin retinol-binding protein (RBP), the specific carrier... (Review)
Review
Transthyretin (TTR, formerly called prealbumin), one of the transporters of the hormone thyroxine and the lipocalin retinol-binding protein (RBP), the specific carrier of the vitamin, are known to form, under physiological conditions, a macromolecular complex that is believed to play an important physiological role: prevention of glomerular filtration of the low molecular weight RBP in the kidneys. The physiological significance of complex formation is discussed first, followed by a brief description of the three-dimensional structure of the two participating proteins. The two X-ray models of the complex available are subsequently discussed and compared and finally the non-crystallographic evidence that supports these models is reviewed.
Topics: Animals; Humans; Models, Molecular; Prealbumin; Protein Conformation; Retinol-Binding Proteins; X-Ray Diffraction
PubMed: 11058748
DOI: 10.1016/s0167-4838(00)00140-0 -
Clinics in Laboratory Medicine Sep 1993TBG, TTR, and albumin are quantitatively the most important thyroid hormone binding proteins in humans. Only a minute fraction of T3 and T4 circulates unbound, but it is... (Review)
Review
TBG, TTR, and albumin are quantitatively the most important thyroid hormone binding proteins in humans. Only a minute fraction of T3 and T4 circulates unbound, but it is this free hormone that is metabolically active at the tissue level, and, therefore, responsible for thyroid status. Inherited or acquired variations in the concentration or affinity of these proteins may produce substantial changes in serum total thyroid hormone levels but do not affect serum free thyroid hormone concentrations and, therefore, do not influence actual thyroid status. Thus, thyroid hormone-binding protein abnormalities must be suspected when abnormally elevated or diminished total thyroid hormone concentrations are encountered in clinically euthyroid subjects. This is crucial to avoid erroneous and potentially detrimental treatments for hyperthyroidism or hypothyroidism.
Topics: Biological Transport; Carrier Proteins; Genetic Variation; Humans; Prealbumin; Serum Albumin; Thyroid Hormones; Thyroxine-Binding Proteins
PubMed: 8222576
DOI: No ID Found -
Computers in Biology and Medicine Mar 2023Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or...
Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or temperature variations can compromise intramolecular stability generating misfolding or unfolding proteins with consequent impairment of functionality and the triggering of pathological states. The intramolecular HINT scoring function recently implemented and validated, is proposed as a rapid and sensitive method for the evaluation of different conformational states characterizing destabilization processes. In this work, the stability of Transthyretin, whose denaturation is related to amyloid fibril formation, is evaluated by generating multiple structural mutated models under different pH conditions in comparison with experimental data. These results suggest that the HINT scoring function can be used for an accurate and rapid evaluation and computational prediction of the effects of structural changes on any protein system.
Topics: Prealbumin; Amyloid; Comprehension; Protein Denaturation; Protein Folding
PubMed: 36805224
DOI: 10.1016/j.compbiomed.2023.106667 -
FEBS Letters Jun 1975
Review
Topics: Animals; Microsomes, Liver; Prealbumin; Radioimmunoassay; Rats; Serum Albumin
PubMed: 1093878
DOI: 10.1016/0014-5793(75)80056-1