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Cells Jul 2021Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is... (Review)
Review
Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.
Topics: Amyloid; Amyloidosis; Animals; Arthritis; Cardiovascular Diseases; Humans; Osteoporosis; Oxidative Stress; Prealbumin; Protein Conformation; Protein Stability
PubMed: 34359938
DOI: 10.3390/cells10071768 -
Protein and Peptide Letters Apr 2005High hydrostatic pressure (HHP) is a powerful tool to study protein folding and the dynamics and structure of folding intermediates. Aggregates and amyloids, derived... (Review)
Review
High hydrostatic pressure (HHP) is a powerful tool to study protein folding and the dynamics and structure of folding intermediates. Aggregates and amyloids, derived from partially folding intermediates at the junction between productive and off-pathway folding, have been studied as well, which promises better understanding of the protein misfolding diseases. Here is summarized the recent data we have collected with transthyretin under pressure.
Topics: Amyloidosis; Hydrostatic Pressure; Prealbumin; Thermodynamics
PubMed: 15777273
DOI: 10.2174/0929866053587200 -
Nature Reviews. Drug Discovery Nov 2015The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the... (Review)
Review
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure-activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.
Topics: Animals; Biological Factors; Humans; Neurodegenerative Diseases; Prealbumin; Protein Aggregation, Pathological; Protein Folding; Protein Transport; Structure-Activity Relationship; Treatment Outcome
PubMed: 26338154
DOI: 10.1038/nrd4593 -
Human Mutation 1995To date, over 40 different mutations in transthyretin (TTR) have been associated with amyloid deposition. The major unresolved problem is the correlation between the... (Review)
Review
To date, over 40 different mutations in transthyretin (TTR) have been associated with amyloid deposition. The major unresolved problem is the correlation between the clinical heterogeneity and the genetic heterogeneity. For instance, whereas some mutations produce neuropathy and some give rise to cardiomyopathy, others produce vitreous opacities, the vast majority being neuropathic. Moreover, some mutations are not amyloidogenic but are responsible to hyperthyroxinemias (by virtue of the protein function in thyroid transport), whereas others are apparently nonpathogenic. The study of TTR variants is very important to the understanding of the amyloid formation process and to establish a relationship between the structure and function of the molecule. The results of current TTR mutation screening programs and their characterization are summarized.
Topics: Alleles; Amyloidosis; Chromosomes, Human, Pair 18; Female; Gene Frequency; Genetic Heterogeneity; Humans; Male; Mutation; Prealbumin; Protein Structure, Tertiary
PubMed: 7599630
DOI: 10.1002/humu.1380050302 -
Biochemical and Biophysical Research... Jul 1984Serum prealbumin isolated from a Japanese patient with familial amyloidotic polyneuropathy (FAP) has been found to consist of a mixture of normal prealbumin and a... (Comparative Study)
Comparative Study
Serum prealbumin isolated from a Japanese patient with familial amyloidotic polyneuropathy (FAP) has been found to consist of a mixture of normal prealbumin and a prealbumin variant which contains a methionine for valine substitution at position 30. The prealbumin variant in the serum is identical to the prealbumin variant derived from amyloid fibrils of a Japanese FAP patient. FAP likely results from the deposition of abnormal serum prealbumin in various organs as amyloid fibrils.
Topics: Adult; Amino Acid Sequence; Amino Acids; Amyloidosis; Chromatography, High Pressure Liquid; Genetic Variation; Humans; Male; Peptide Fragments; Peripheral Nervous System Diseases; Prealbumin; Reference Values
PubMed: 6087810
DOI: 10.1016/s0006-291x(84)80092-3 -
International Journal of Molecular... Jun 2019Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form... (Review)
Review
Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.
Topics: Amyloidogenic Proteins; Amyloidosis; Biomarkers; Diagnosis, Differential; Disease Management; Humans; Mutation; Prealbumin; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; Workflow
PubMed: 31216785
DOI: 10.3390/ijms20122982 -
Nature Communications Feb 2019Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer...
Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer protective effects. The molecular basis underlying the vastly different fibrillation behaviours of these TTR mutants is poorly understood. Here, on the basis of neutron crystallography, native mass spectrometry and modelling studies, we propose a mechanism whereby TTR can form amyloid fibrils via a parallel equilibrium of partially unfolded species that proceeds in favour of the amyloidogenic forms of TTR. It is suggested that unfolding events within the TTR monomer originate at the C-D loop of the protein, and that destabilising mutations in this region enhance the rate of TTR fibrillation. Furthermore, it is proposed that the binding of small molecule drugs to TTR stabilises non-amyloidogenic states of TTR in a manner similar to that occurring for the protective mutants of the protein.
Topics: Amyloidosis; Humans; Kinetics; Models, Molecular; Mutation; Prealbumin; Protein Conformation; Protein Folding; Protein Unfolding
PubMed: 30804345
DOI: 10.1038/s41467-019-08609-z -
Journal of Medicinal Chemistry Feb 2019Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer...
Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer precede amyloid fibril formation, development of a small molecule that binds to TTR and stabilizes the TTR tetramer is an efficient strategy for the treatment of amyloidosis. Here, we report our discovery of the anti-TTR amyloidogenesis activities of crown ethers. X-ray crystallographic analysis, binding assay, and chemical cross-linking assay showed that 4'-carboxybenzo-18C6 (4) stabilized the TTR tetramer by binding to the allosteric sites on the molecular surface of the TTR tetramer. In addition, 4 synergistically increased the stabilization activity of diflunisal, one of the most potent TTR amyloidogenesis inhibitors. These experimental evidences establish that 4 is a valuable template compound as an allosteric inhibitor of TTR amyloidogenesis.
Topics: Allosteric Site; Amyloidogenic Proteins; Crown Ethers; Crystallography, X-Ray; Diflunisal; Drug Discovery; Humans; Prealbumin; Protein Binding; Protein Multimerization
PubMed: 30688456
DOI: 10.1021/acs.jmedchem.8b01700 -
Current Medicinal Chemistry 2012Hereditary amyloidogenic transthyretin (TTR) (ATTR) amyloidosis is an autosomal dominant form of fatal hereditary amyloidosis. Owing to progress in biochemical and... (Review)
Review
Hereditary amyloidogenic transthyretin (TTR) (ATTR) amyloidosis is an autosomal dominant form of fatal hereditary amyloidosis. Owing to progress in biochemical and molecular genetic analyses, this disease is now believed to occur worldwide. As of today, reports of about 120 different points of single or double mutations, or a deletion in the TTR gene have been reported, and several different phenotypes of ATTR amyloidosis have been documented. In addition, since liver transplantation has been established to halt the progression of hereditary ATTR amyloidosis in the early stage, rapid and reliable diagnostic system for ATTR amyloidosis is needed. On the other hand, senile systemic amyloidosis (SSA) derived from wild-type (WT) TTR affects primarily in the heart and lungs and occasionally in carpal ligaments in the elderly. To perform accurate diagnosis and effective treatments, we should distinguish between hereditary ATTR amyloidosis and SSA by means of genetic and proteomic analyses. The liver transplantation for hereditary ATTR amyloidosis has become a well-established treatment, because the main source of serum variant TTR is shut out. However, this treatment has several problems, such as expensive medical costs, lifelong administration of immunosuppressants, non-indication for the mutated-TTR gene carriers without clinical symptoms, shortage of liver donors, and further development of cardiac and ocular disorders. Therefore, we and other ATTR amyloidosis research groups have been investigating the possibility of stabilization of variant TTR, gene therapy, and immunotherapy for ATTR amyloidosis on the basis of TTR amyloid formation mechanism. We present here the current diagnostic procedure and therapeutic approaches for the disease.
Topics: Amyloidosis; Genetic Therapy; Humans; Immunotherapy; Liver Transplantation; Prealbumin
PubMed: 22471980
DOI: 10.2174/092986712800269317 -
The Journal of Biological Chemistry Jul 1977
Topics: Amino Acids; Animals; Chromatography, Affinity; Humans; Methods; Molecular Weight; Prealbumin; Precipitin Tests; Rats; Serum Albumin; Ultracentrifugation
PubMed: 873934
DOI: No ID Found