A comparative analysis of 23 structures of the amyloidogenic protein transthyretin

Hörnberg, A.; Eneqvist, Therese; Olofsson, Anders; Lundgren, Erik; Sauer‐Eriksson, A. Elisabeth

doi:10.1006/jmbi.2000.4078

Cited by 202 publications

(270 citation statements)

References 79 publications

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“…13,14 The most severe form of FAP is associated with the L55P variant of TTR, with disease onset occurring in the second decade of life. 17 A comparison of the X-ray crystal structures of wild type, V30M, and L55P TTR does not reveal any differences that can explain the amyloidogenicities of the latter two variants, 18 nor is the function of the variants noticeably compromised. All evidence suggests that these are gain of toxic function diseases associated with the process of amyloid fibril formation.…”

Section: Introductionmentioning

confidence: 98%

Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors

et al. 2001

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Twelve analogues of diclofenac (1), a nonsteroidal antiinflammatory drug and known inhibitor of transthyretin (TTR) amyloid formation, were prepared and evaluated as TTR amyloid formation inhibitors. High activity was exhibited by five of the compounds. Structure-activity relationships reveal that a carboxylic acid is required for activity, but changes in its position as well as the positions of other substituents are tolerated. High-resolution X-ray crystal structures of four of the active compounds bound to TTR were obtained. These demonstrate the significant flexibility with which TTR can accommodate ligands within its two binding sites.

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Section: Introductionmentioning

confidence: 98%

Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors

et al. 2001

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“…8 It has also become apparent that amyloidogenic single-point mutations influence not only TTR dissociation kinetics 9 but yield monomers with lower thermodynamic stability, 8 in spite of the high structural similarity between the mutants and the wildtype protein. 7 Additionally, amyloidogenic TTR variants were shown to produce, in solution and even at neutral pH, higher amounts of partially unfolded monomeric species with enhanced propensity for ordered aggregation into amyloid fibrils. 10,11 Therefore, the conformational stability of the TTR monomers undoubtedly plays a critical role in the process of amyloid formation.…”

Section: Introductionmentioning

confidence: 99%

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

et al. 2010

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Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt-Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT-TTR and L55P-TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P-TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single a-helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation-prone conformations characterized by full displacement of strands C and D from the main b-sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H-bond network and consequent destabilization of the CBEF b-sheet of the b-sandwich; (v) WT forms aggregationcompatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P-TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.

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“…On the other hand, the non-amyloidogenic mutant T119M has been described as an interallelic trans-suppressor variant in compound heterozygotes that alleviates the aggressiveness of V30M disease. 12 -14 Although the resolution of the crystal structure of several amyloidogenic mutants has not shown significant differences from the wt protein, 15,16 several other studies have focused on the mechanisms that could explain their higher propensity to undergo aggregation. 17 -20 It is now well accepted that an amyloidogenic intermediate with an altered conformation occurs prior to fibril formation.…”

Section: Introductionmentioning

confidence: 99%

Hydration and Packing are Crucial to Amyloidogenesis as Revealed by Pressure Studies on Transthyretin Variants that Either Protect or Worsen Amyloid Disease

Gonzales

Palmieri

Valory

et al. 2003

Journal of Molecular Biology

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The formation of amyloid aggregates is the hallmark of the amyloidogenic diseases. Transthyretin (TTR) is involved in senile systemic amyloidosis (wild-type protein) and familial amyloidotic polyneuropathy (point mutants). Through the use of high hydrostatic pressure (HHP), we compare the stability among wild-type (wt) TTR, two disease-associated mutations (V30M and L55P) and a trans-suppressor mutation (T119M). Our data show that the amyloidogenic conformation, easily populated in the disease-associated mutant L55P, can be induced by a cycle of compression-decompression with the wt protein rendering the latter highly amyloidogenic. After decompression, the recovered wt structure has weaker subunit interactions (loosened tetramer, T 4 p ) and presents a stability similar to L55P, suggesting that HHP induces a defective fold in the wt protein, converting it to an altered conformation already present in the aggressive mutant, L55P. On the other hand, glucose, a chemical chaperone, can mimic the trans-suppression mutation by stabilizing the native state and by decreasing the amyloidogenic potential of the wt TTR at pH 5.0. The sequence of pressure stability observed was: L55P , V30M , wt p T119M. The pressure dissociation of L55P at 1 8C exhibited dependence on protein concentration, allowing us to assess the volume change of association and the free-energy change. After a cycle of compression-decompression at 37 8C and pH 5.6 or lower, all amyloidogenic variants underwent aggregation. Binding of bis-(8-anilinonaphthalene-1-sulfonate) (bis-ANS) revealed that the species formed under pressure retained part of its tertiary contacts (except T119M). However, at neutral pH, where aggregation did not take place after decompression, bis-ANS binding was absent. Thus, TTR has to experience this partially folded conformation to undergo aggregation after decompression. Overall, our studies provide evidence that amyloidogenesis correlates with less packed structures (larger volume changes) and high susceptibility to water infiltration. The hydration effects can be counteracted by osmolytes or by a specific mutation.

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A comparative analysis of 23 structures of the amyloidogenic protein transthyretin

Cited by 202 publications

References 79 publications

Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors

Synthesis, Structure, and Activity of Diclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

Hydration and Packing are Crucial to Amyloidogenesis as Revealed by Pressure Studies on Transthyretin Variants that Either Protect or Worsen Amyloid Disease

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