Transthyretin mutations in health and disease

João, Maria; Saraiva, Maria João

doi:10.1002/humu.1380050302

Cited by 195 publications

(28 citation statements)

References 42 publications

(10 reference statements)

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“…Transthyretin carries a substantial quantity of thyroxine (T 4 ) in the CSF, but in the blood, the two T 4 -binding sites of TTR are 99% unoccupied owing to the presence of additional T 4 carriers 280 . Substantial biophysical data suggest that in the case of the 125+ distinct mutations linked to the familial TTR amyloidoses 281 (http://amyloidosismutations.com/mut-attr.php), incorporation of mutant TTR subunits into a TTR tetramer otherwise composed of WT subunits destabilizes the heterotetramer—leading to faster TTR tetramer dissociation kinetics (kinetic destabilization), an increased population of misfolded aggregation-prone TTR monomer (thermodynamic destabilization), or both 282, 283 . Kinetic destabilization is especially relevant for aggregation and likely for disease progression, since TTR tetramer dissociation is the rate-limiting step in the amyloidogenesis cascade (see figure) 25, 26 .…”

Section: Figurementioning

confidence: 99%

Targeting protein aggregation for the treatment of degenerative diseases

Eisele

Monteiro

Fearns

et al. 2015

Nat Rev Drug Discov

347

333

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The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, collectively called 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 pharmacologic and genetic evidence now support protein aggregation as the cause of post-mitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation, as well as the structure-activity relationships underlying proteotoxicity are needed to develop future disease-modifying therapies.

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Section: Figurementioning

confidence: 99%

Targeting protein aggregation for the treatment of degenerative diseases

Eisele

Monteiro

Fearns

et al. 2015

Nat Rev Drug Discov

347

333

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“…1–3 Extracelluar deposition of TTR aggregates in various organs including heart, lung, and peripheral nerves is associated with senile systemic amyloidosis, familial amyloidotic polyneuropathy, familial amyloid cardiomyopathy, and rarely central nervous system selective amyloidosis. 4–6 The TTR amyloidoses exhibit extreme variations of the disease phenotype. 4,7–9 For example, aggregation of wild-type (WT) TTR affects primarily the heart and lung, causing senile systemic amyloidosis that affects nearly 25% of the population over age 80.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Mutations Induce Partial Structural Changes in the Native β-Sheet Structure of Transthyretin and Accelerate Aggregation

Lim

Dasari

et al. 2017

Biochemistry

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Amyloid formation of natively folded proteins involves global and/or local unfolding of the native state to form aggregation-prone intermediates. Here we report solid-state NMR structural studies of amyloid derived from wild-type (WT) and more aggressive mutant forms of transthyretin (TTR) to investigate the structural changes associated with effective TTR aggregation. We employed selective 13C-labeling schemes to investigate structural features of β-structured core regions in amyloid states of WT and two mutant forms (V30M and L55P) of TTR. Analyses of the 13C-13C correlation solid-state NMR spectra revealed that WT TTR aggregates contain an amyloid core consisting of native-like CBEF and DAGH β-sheet structures and the mutant TTR amyloids adopt a similar amyloid core structure with native-like CBEF and AGH β-structures. However, the V30M mutant amyloid was shown to have a different DA β-structure. In addition, strand D is more disordered even in the native state of L55P TTR, indicating that the pathogenic mutations affect the DA β-structure, leading to more effective amyloid formation. The NMR results are consistent with our mass spectrometry-based thermodynamic analyses that showed the amyloidogenic precursor states of WT and mutant TTRs adopt folded structures, but the mutant precursor states are less stable than that of WT TTR. Analyses of the oxidation rate of methionine sidechain also revealed that the sidechain of residue Met-30 pointing between strands D and A is not protected from the oxidation in V30M mutant, while protected in the native state, supporting that the DA β-structure might be disrupted in V30M mutant amyloid.

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“…The biosynthesis, the various structural domains, cleavage sites and a few selected key mutations in hTTR are shown schematically in Figure 1. The above single monomeric chain forms a strong tetrameric complex (Calculated MW ~55,044 Da) that exhibits its physiological and biological activity [33][34][35]. A recent study with hTTR wild type as well as its key physiological mutant variants suggested that each monomeric form of hTTR is proteolytically cleaved likely by a trypsin like enzyme and this site may be located not far from 50 amino acids from the N-terminal end.…”

Section: Peptide Designmentioning

confidence: 99%

“…Along with this wild type peptide we also designed two additional peptides which contain the physiologically relevant mutations Ser 52 /Pro and Thr 49 /Ala. The rationale for this is based on the published observation that implicated the first mutation (Ser 52 /Pro) to most pathogenic state of amyloidosis followed by the second mutation (Thr 49 /Ala) [33,35]. A fourth peptide containing Lys 48 / Ala mutation has also been designed in order to examine the importance of basic Lys 48 residue in hTTR proteolysis.…”

Section: Peptide Designmentioning

confidence: 99%

“…It is suggested that such mutations in hTTR lead to instability of its tetrameric structure which ultimately fold apart as monomer that then self-aggregates into fibril structures promoted by its proteolysis [32,33]. It is now well established that pathogenic severity depends on hTTR aggregation rate and it is most aggressive for the rare L 55 P mutation compared to the more common V 30 M mutation [35]. A number of these mutations are depicted in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Proteolytic truncation of human transthyretin linked to amyloidosis is mediated by a trypsin like enzyme: In vitro demonstration using model peptides

Saad¹,

Lu²,

Koya³

et al. 2016

Bio Chem Comp

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Background: A number of human conditions collectively known as amyloidosis were found to be associated with self-aggregation of a specific group of proteins. This fibril like protein aggregates deposit in different tissues including the central nervous system leading to amyloid polyneuropathies (AP), systemic senile amyloidosis (SSA), amyloidotic cardiomyopathy (AC) and carpal tunnel syndrome (CTS). The most common protein in this group is human transthyretin (hTTR). Similar to beta amyloid peptide of Alzheimer's Disease, hTTR forms amyloid type fibrils following its proteolytic cleavage at the C-(carboxy) terminus leading to aggregation. hTTR is normally present in blood where it binds with thyroid hormone thyroxine T4 and Retinol Binding Protein-Vitamin A complex and mediates their transport. It is also present in lower amount in cerebrospinal fluid as a major carrier of thyroxine hormone. Deposition of hTTR fibril aggregates is responsible for SSA usually observed in older population with age >60 years which is regulated by its mutant forms. The exact mechanism of this disorder is still unclear. Studies confirmed that C-terminally truncated hTTR undergoes rapid self-aggregation leading to amyloidosis. The site of this cleavage and the protease involved has not been fully characterized although it is proposed to be at Lys 48 ↓Thr 49 residues.Objective: The major goal of this study is to confirm that hTTR is cleaved by a trypsin like enzyme at the position indicated by vertical arrow Ala-Ser-Gly-Lys 48 ↓Thr 49 -Ser-Glu-Ser and that this cleavage can be blocked by a trypsin-inhibitor. Methods:A 20 mer peptide comprising the wild type sequence from residue (41-60) of hTTR was synthesized, purified by RP-HPLC and fully characterized by mass spectrometry. Three additional mutant peptides namely Lys These results are consistent with those reported for the physiological full length hTTR proteins. Moreover the above cleavage can be blocked efficiently by a trypsin inhibitor (dimethyl formamide), reported for the first time in this study. Energy minimised 3D modeling study revealed that Lys 48 /Ala mutant exhibits a unique structural conformation compared to the corresponding wild type control peptide suggesting its potential role in regulating proteolytic cleavage. Overall our data confirmed the key role of a trypsin like enzyme in hTTR proteolysis leading to its truncation which facilitates its self-aggregation leading to amyloidosis. The study also highlighted a potential therapeutic strategy for hTTR associated amyloidosis by targeting this enzyme with specific inhibitors.

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Transthyretin mutations in health and disease

Cited by 195 publications

References 42 publications

Targeting protein aggregation for the treatment of degenerative diseases

Targeting protein aggregation for the treatment of degenerative diseases

Pathogenic Mutations Induce Partial Structural Changes in the Native β-Sheet Structure of Transthyretin and Accelerate Aggregation

Proteolytic truncation of human transthyretin linked to amyloidosis is mediated by a trypsin like enzyme: In vitro demonstration using model peptides

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