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Comparative Biochemistry and... Feb 1997Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this... (Review)
Review
Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this partitioning and establish intravascular, protein-bound thyroxine pools. These are far larger than the free thyroxine pools. In larger eutherians, proteins specifically binding thyroxine are albumin, transthyretin, and thyroxine-binding globulin. Some binding of thyroxine can also occur to lipoproteins. During evolution, transthyretin synthesis first appeared in the choroid plexus of the stem reptiles, about 300 million years ago. Transthretin synthesis in the liver evolved much later, independently, in birds, eutherians and some marsupial species. Analysis of 57 human transthyretin variants suggests that most mutations in transthyretin are not compatible with its normal metabolism and lead to its deposition as amyloid. Analysis of transthyretin or its gene in 20 different species shows that evolutionary changes of transthyretin predominantly occurred near the N-termini. A change in RNA splicing between exon 1 and exon 2 led to a decrease in hydrophobicity and length of the N-termini. It is proposed that the selection pressure producing these changes was the need for a more effective prevention of thyroxine partitioning into lipids. Lipid pools increased during evolution with the increases in relative sizes of brains and internal organs and changes in lipid composition of membranes in ectothermic and endothermic species.
Topics: Amino Acid Sequence; Animals; Brain; Carrier Proteins; Evolution, Molecular; Gene Expression; Humans; Liver; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Molecular Structure; Phylogeny; Prealbumin; Protein Conformation; Thyroid Hormones; Thyroid Hormone-Binding Proteins
PubMed: 9159878
DOI: 10.1016/s0305-0491(96)00212-x -
Clinical Chemistry and Laboratory... Dec 2002We have expressed transthyretin (TTR) mutants which have significantly destabilised tetramers that aggregate into amyloid fibrils via a series of intermediates. We used...
We have expressed transthyretin (TTR) mutants which have significantly destabilised tetramers that aggregate into amyloid fibrils via a series of intermediates. We used atomic force microscopy to follow the morphology of aggregates during fibril formation. Initially, amorphous aggregates are formed that subsequently mature into fibrillar structures. This observation is interpreted as an optimisation of beta-strand registers. The rate of aggregation and maturation is highly temperature-dependent suggesting that entropic forces significantly contribute to stability. In addition, we identified a correlation between the presence of early formed aggregates of TTR and cytotoxicity. The toxic response was mediated via an apoptotic mechanism. The fact that early formed amorphous aggregates, but not more mature fibrils, exert a toxic response suggests that the rate of fibril formation may be a critical parameter. We propose that a slow rate of aggregation facilitates an increased concentration of a toxic intermediate.
Topics: Amyloid; Apoptosis; HeLa Cells; Humans; Microscopy, Atomic Force; Mutation; Prealbumin; Protein Binding; Protein Folding
PubMed: 12553429
DOI: 10.1515/CCLM.2002.219 -
The FEBS Journal Oct 2009The structure of the thyroid hormone distributor protein, transthyretin, has been highly conserved during the evolution of vertebrates. Over the last decade, studies... (Review)
Review
The structure of the thyroid hormone distributor protein, transthyretin, has been highly conserved during the evolution of vertebrates. Over the last decade, studies into the evolution of transthyretin have revealed the existence of a transthyretin homolog, transthyretin-like protein, in all kingdoms. Phylogenetic studies have suggested that the transthyretin gene in fact arose as a result of a duplication of the transthyretin-like protein gene in early protochordate evolution. Structural studies of transthyretin-like proteins from various organisms have revealed the remarkable conservation of the transthyretin-like protein/transthyretin fold. The only significant differences between the structures of transthyretin-like protein and transthyretin were localized to the dimer-dimer interface and indicated that thyroid hormones could not be bound by transthyretin-like protein. All transthyretin-like proteins studied to date have been demonstrated to function in purine metabolism by hydrolysing the oxidative product of uric acid, 5-hydroxyisourate. The residues characterizing the catalytic site in transthyretin-like proteins are 100% conserved in all transthyretin-like protein sequences but are absent in transthyretins. Therefore, it was proposed that following duplication of the transthyretin-like protein gene, loss of these catalytic residues resulted in the formation of a deep, negatively charged channel that runs through the centre of the transthyretin tetramer. The results thus demonstrate the remarkable evolution of the transthyretin-like protein/transthyretin protein from a hydrolytic enzyme to a thyroid hormone distributor protein.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Bacteria; Binding Sites; Conserved Sequence; Eukaryotic Cells; Evolution, Molecular; Gene Duplication; Humans; Models, Molecular; Molecular Sequence Data; Prealbumin; Purines; Sequence Homology, Amino Acid; Static Electricity; Uric Acid; Vertebrates
PubMed: 19725880
DOI: 10.1111/j.1742-4658.2009.07246.x -
International Review of Cytology 2007Advances in four areas of transthyretin (TTR) research result in this being a timely review. Developmental studies have revealed that TTR is synthesized in all classes... (Review)
Review
Advances in four areas of transthyretin (TTR) research result in this being a timely review. Developmental studies have revealed that TTR is synthesized in all classes of vertebrates during development. This leads to a new hypothesis on selection pressure for hepatic TTR synthesis during development only, changing the previous hypotheses from "onset" of hepatic TTR synthesis in adulthood to "maintaining" hepatic TTR synthesis into adulthood. Evolutionary studies have revealed the existence of TTR-like proteins (TLPs) in nonvertebrate species and elucidated some of their functions. Consequently, TTR is an excellent model for the study of the evolution of protein structure, function, and localization. Studies of human diseases have demonstrated that TTR in the cerebrospinal fluid can form amyloid, but more recently there has been recognition of the roles of TTR in depression and Alzheimer's disease. Furthermore, amyloid mutations in human TTR that are the normal residues in other species result in cardiac deposition of TTR amyloid in humans. Finally, a revised model for TTR-thyroxine entry into the cerebrospinal fluid via the choroid plexus, based on data from studies in TTR null mice, is presented. This review concentrates on TTR and its thyroid hormone binding, in development and during evolution, and summarizes what is currently known about TLPs and the role of TTR in diseases affecting the brain.
Topics: Amino Acid Sequence; Animals; Base Sequence; Evolution, Molecular; Gene Expression Regulation, Developmental; Humans; Molecular Sequence Data; Prealbumin; Thyroid Hormones; Vertebrates
PubMed: 17338921
DOI: 10.1016/S0074-7696(07)58003-4 -
Journal of Neuroendocrinology May 2015Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). TTR synthesised in the liver is secreted into the bloodstream and distributes THs... (Review)
Review
Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). TTR synthesised in the liver is secreted into the bloodstream and distributes THs around the body, whereas TTR synthesised in the choroid plexus is involved in movement of thyroxine from the blood into the cerebrospinal fluid and the distribution of THs in the brain. This is important because an adequate amount of TH is required for normal development of the brain. Nevertheless, there has been heated debate on the role of TTR synthesised by the choroid plexus during the past 20 years. We present both sides of the debate and how they can be reconciled by the discovery of TH transporters. New roles for TTR have been suggested, including the promotion of neuroregeneration, protection against neurodegeneration, and involvement in schizophrenia, behaviour, memory and learning. Recently, TTR synthesis was revealed in neurones and peripheral Schwann cells. Thus, the synthesis of TTR in the central nervous system (CNS) is more extensive than previously considered and bolsters the hypothesis that TTR may play wide roles in neurobiological function. Given the high conservation of TTR structure, function and tissue specificity and timing of gene expression, this implies that TTR has a fundamental role, during development and in the adult, across vertebrates. An alarming number of 'unnatural' chemicals can bind to TTR, thus potentially interfering with its functions in the brain. One role of TTR is delivery of THs throughout the CNS. Reduced TH availability during brain development results in a reduced IQ. The combination of the newly discovered sites of TTR synthesis in the CNS, the increasing number of neurological diseases being associated with TTR, the newly discovered functions of TTR and the awareness of the chemicals that can interfere with TTR biology render this a timely review on TTR in neurobiology.
Topics: Animals; Brain; Central Nervous System; Central Nervous System Diseases; Choroid Plexus; Cognition; DNA; Endocrine Disruptors; Humans; Neurons; Prealbumin; Retinol-Binding Proteins; Schwann Cells; Thyroid Hormones; Vertebrates
PubMed: 25737004
DOI: 10.1111/jne.12271 -
The Journal of Clinical Investigation Dec 1985A transthyretin variant with a methionine for valine substitution at position 30 [TTR(Met30)] is found in Portuguese patients with familial amyloidotic polyneuropathy...
A transthyretin variant with a methionine for valine substitution at position 30 [TTR(Met30)] is found in Portuguese patients with familial amyloidotic polyneuropathy (FAP). Effective, rapid, small- and semimicro-scale (immunoblotting) procedures were developed to determine whether or not TTR(Met30) is present in the plasma of an individual subject. The immunoblotting procedure employs only 0.10 ml of serum and can serve as a reliable procedure for the screening of large numbers of persons for the presence of TTR(Met30). In family studies of seven FAP kindreds, TTR(Met30) was found in 21 out of 41 asymptomatic FAP offspring, and its presence was not related to either age or sex. Thus, the mutant TTR segregated in accordance with the known autosomal dominant mode of inheritance of FAP. Total plasma TTR levels were not reduced in asymptomatic FAP offspring who were carriers of TTR(Met30), and no difference was observed between carriers and noncarriers of the mutant TTR. The ratios of the variant to normal TTR in plasma were estimated in asymptomatic FAP offspring and were similar to those found in FAP patients. In contrast, TTR(Met30) was relatively enriched in cerebrospinal fluid samples from two FAP patients. The significance of this finding is not known, but might relate to the preferential deposition of amyloid in the nervous system in FAP. A limited study was conducted involving simultaneous analysis of both stored (collected in 1975) and fresh serum from 20 FAP offspring, all of whom had been asymptomatic in 1975. In every subject, the results obtained with the stored and the fresh serum samples were in agreement. Six of these subjects developed clinical FAP since 1975; TTR(Met30) was present in each of these subjects. These several studies strongly suggest that the presence of TTR(Met30) in plasma constitutes a predictive biochemical marker of FAP in the preclinical phase of the disease.
Topics: Adolescent; Adult; Amino Acid Sequence; Amyloidosis; Child; Female; Genetic Carrier Screening; Humans; Immunosorbent Techniques; Male; Nervous System Diseases; Pedigree; Prealbumin
PubMed: 3908483
DOI: 10.1172/JCI112224 -
Circulation Sep 2021
Topics: Amyloidosis; Heart; Humans; Prealbumin; Radionuclide Imaging
PubMed: 34570590
DOI: 10.1161/CIRCULATIONAHA.121.055517 -
Current Drug Targets. CNS and... Oct 2005In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel... (Review)
Review
In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4'-iodo-4'-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.
Topics: Amyloid; Amyloidosis; Animals; Humans; Prealbumin; Protein Folding; Protein Isoforms
PubMed: 16266291
DOI: 10.2174/156800705774322076 -
Redox Biology Oct 2022Human transthyretin (TTR) is a tetrameric protein transporting thyroid hormones and retinol. TTR is a neuroprotective factor and sensor of oxidative stress which...
Human transthyretin (TTR) is a tetrameric protein transporting thyroid hormones and retinol. TTR is a neuroprotective factor and sensor of oxidative stress which stability is diminished due to mutations and aging, leading to amyloid deposition. Adverse environmental conditions, such as redox and metal ion imbalances, induce destabilization of the TTR structure. We have previously shown that the stability of TTR was disturbed by Ca and other factors, including DTT, and led to the formation of an intrinsic fluorophore(s) emitting blue light, termed deep blue autofluorescence (dbAF). Here, we show that the redox state of TTR affects the formation dynamics and properties of dbAF. Free thiols lead to highly unstable subpopulations of TTR and the frequent ocurrence of dbAF. Oxidative conditions counteracted the destabilizing effects of free thiols to some extent. However, strong oxidative conditions led to modifications of TTR, which altered the stability of TTR and resulted in unique dbAF spectra. Riboflavin and/or riboflavin photoproducts bound to TTR and crosslinked TTR subunits. Riboflavin-sensitized photooxidation increased TTR unfolding, while photooxidation, either in the absence or presence of riboflavin, increased proteolysis and resulted in multiple oxidative modifications and dityrosine formation in TTR molecules. Therefore, oxidation can switch the role of TTR from a protective to pathogenic factor.
Topics: Amyloid; Humans; Oxidation-Reduction; Prealbumin; Riboflavin; Sulfhydryl Compounds; Vitamin A
PubMed: 35987087
DOI: 10.1016/j.redox.2022.102434 -
Journal of the American Geriatrics... Dec 2022Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and...
BACKGROUND
Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype.
METHODS
A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM-MS). The phenotype was assessed by disease-specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36-question short-form health survey, as well as biochemical measures (TTR, retinol-binding protein, and TTR stability). Cardiac testing included technetium-99m-pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity.
RESULTS
Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those <75 years (22.3%, p < 0.05). LCM-MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality-of-life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n = 10), one subject had cardiac involvement by scintigraphy.
CONCLUSIONS
Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those >75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.
Topics: Female; Humans; Male; Amyloid; Amyloidosis; Cardiomyopathies; Constriction, Pathologic; Prealbumin; Prospective Studies; Spinal Stenosis; Middle Aged; Aged
PubMed: 35929177
DOI: 10.1111/jgs.17976