Destabilisation of the structure of transthyretin is driven by Ca2+

Wieczorek, Elźbieta; Kędracka–Krok, Sylwia; Bystranowska, Dominika; Ptak, Maciej; Wiak, Karolina; Wygralak, Zofia; Jankowska, Urszula; Ożyhar, Andrzej

doi:10.1016/j.ijbiomac.2020.10.199

Cited by 13 publications

(26 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TTR stability strongly relies on the hydrogen bonding network formed by intramolecular interactions with water molecules and intermolecular interactions with the solvent [ 45 , 46 ]. The flexibility of the loops (particularly the DE loop) is critical for TTR stability, and conformational fluctuations contribute to aggregation propensity of TTR [ 47 , 48 , 49 , 50 , 51 ]. The binding of thyroxine and some other ligands (resveratrol and curcumin) increases structural stability of TTR [ 21 , 22 , 52 ].…”

Section: Structural Stability Cleavage and Amyloidogenesis Of Ttrmentioning

confidence: 99%

“…The binding of thyroxine and some other ligands (resveratrol and curcumin) increases structural stability of TTR [ 21 , 22 , 52 ]. On the other hand, proper TTR structure is negatively affected by oxidative modifications, aging, metal cations (including Ca 2+ ), and most of the known TTR mutations [ 21 , 47 , 53 , 54 , 55 , 56 , 57 ]. Destabilizing mutations negatively affect the association between TTR subunits, which leads to the dissociation of the tetramer to dimers, followed by their fast decomposition to monomers [ 57 , 58 ], as shown in Figure 1 .…”

Section: Structural Stability Cleavage and Amyloidogenesis Of Ttrmentioning

confidence: 99%

“…In particular, the investigation of the role of physiological factors in the regulation of TTR stability should be continued. Amyloid formation can be associated with metal-induced oxidation (Zn 2+ , Cu 2+ , Fe 3+ , Mn 2+ , Co 2+ , and Ca 2+ ) and subsequent N -terminal backbone fragmentation of TTR molecules [ 47 , 100 ]. Metal-induced cleavage of the N-terminus (mostly at the Cys10-Pro11 peptide bond) results in simultaneous appearance of new conformers and increases the propensity of TTR to aggregate [ 47 , 100 ].…”

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

“…Amyloid formation can be associated with metal-induced oxidation (Zn 2+ , Cu 2+ , Fe 3+ , Mn 2+ , Co 2+ , and Ca 2+ ) and subsequent N -terminal backbone fragmentation of TTR molecules [ 47 , 100 ]. Metal-induced cleavage of the N-terminus (mostly at the Cys10-Pro11 peptide bond) results in simultaneous appearance of new conformers and increases the propensity of TTR to aggregate [ 47 , 100 ]. Particular attention should be directed toward the role of Ca 2+ in the stability of TTR structure and function because Ca 2+ regulates many essential physiological processes of the cells, tissues, and organs.…”

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

“…TTR oligomers were also shown to be internalized into the cells (i.e., cardiomyocytes) [ 83 ]. On the other hand, high concentrations of Ca 2+ induce destabilization of TTR tetramers, contributing to TTR oligomerization and amyloid formation [ 47 ]. Therefore, there is a bidirectional relationship between TTR stability (and, at least indirectly, TTR function) and intra- and extracellular Ca 2+ pools.…”

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

See 4 more Smart Citations

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

Wieczorek

Ożyhar

2021

Cells

Self Cite

View full text Add to dashboard Cite

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 Ca2+. 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 Ca2+, 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.

show abstract

Section: Structural Stability Cleavage and Amyloidogenesis Of Ttrmentioning

confidence: 99%

Section: Structural Stability Cleavage and Amyloidogenesis Of Ttrmentioning

confidence: 99%

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

Section: Link Between Ttr and Ca 2+mentioning

confidence: 99%

See 3 more Smart Citations

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

Wieczorek

Ożyhar

2021

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser

et al. 2023

View full text Add to dashboard Cite

Transthyretin (TTR)‐related amyloidosis (ATTR) is a syndrome of diseases characterized by the extracellular deposition of fibrillar materials containing TTR variants. Ala97Ser (A97S) is the major mutation reported in Taiwanese ATTR patients. Here, we combine atomic resolution structural information together with the biochemical data to demonstrate that substitution of polar Ser for a small hydrophobic side chain of Ala at residue 97 of TTR largely influences the local packing density of the FG‐loop, thus leading to the conformational instability of native tetramer, the increased monomeric species, and thus the enhanced amyloidogenicity of apo‐A97S. Based on calorimetric studies, the tetramer destabilization of A97S can be substantially altered by interacting with native stabilizers via similarly energetic patterns compared to that of wild‐type (WT) TTR; however, stabilizer binding partially rearranges the networks of hydrogen bonding in TTR variants while FG‐loops of tetrameric A97S still remain relatively flexible. Moreover, TTR in complexed with holo‐retinol binding protein 4 is slightly influenced by the structural and dynamic changes of FG‐loop caused by A97S substitution with an approximately five‐fold difference in binding affinity. Collectively, our findings suggest that the amyloidogenic A97S mutation destabilizes TTR by increasing the flexibility of the FG‐loop in the monomer, thus modulating the rate of amyloid fibrillization.

show abstract

Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

et al. 2022

View full text Add to dashboard Cite

Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. “Amyloid seeds” are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.

show abstract

Destabilisation of the structure of transthyretin is driven by Ca2+

Cited by 13 publications

References 76 publications

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser

Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis

Contact Info

Product

Resources

About