The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin

Sant’Anna, Ricardo; Braga, Carolina A.; Varejão, Nathalia; Pimenta, Karinne M.; Graña-Montes, Ricardo; Alves, Aline A.; Cortines, Juliana R.; Cordeiro, Yraima; Ventura, Salvador; Foguel, Débora

doi:10.1074/jbc.m114.563981

Cited by 41 publications

(37 citation statements)

References 70 publications

(89 reference statements)

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“…The quantity of information carried by the amino acid sequence is insufficient to unambiguously determine the conformation of each residue [58][59][60]. This work postulates that the aqueous environment remains an integral factor in the folding process and compensates for the observed shortfall in information [9,15,[58][59][60].…”

Section: Discussionmentioning

confidence: 95%

“…The same mechanism can be adopted for the analysis of mutation influence on the resultant stability of particular β-fragments of transthyrein [58].…”

Section: Therapymentioning

confidence: 99%

“…The same mechanism can be adopted for the analysis of mutation influence on the resultant stability of particular β-fragments of transthyrein [58]. Hypothetically, in order to arrest axial propagation of the fibril, we should insert a set of hydrophilic residues along the entire length of the peptide.…”

Section: Therapymentioning

confidence: 99%

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Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Roterman

Banach

Kalinowska

et al. 2016

Entropy

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Abstract:The aqueous environment is a pervasive factor which, in many ways, determines the protein folding process and consequently the activity of proteins. Proteins are unable to perform their function unless immersed in water (membrane proteins excluded from this statement). Tertiary conformational stabilization is dependent on the presence of internal force fields (nonbonding interactions between atoms), as well as an external force field generated by water. The hitherto the unknown structuralization of water as the aqueous environment may be elucidated by analyzing its effects on protein structure and function. Our study is based on the fuzzy oil drop model-a mechanism which describes the formation of a hydrophobic core and attempts to explain the emergence of amyloid-like fibrils. A set of proteins which vary with respect to their fuzzy oil drop status (including titin, transthyretin and a prion protein) have been selected for in-depth analysis to suggest the plausible mechanism of amyloidogenesis.

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Section: Discussionmentioning

confidence: 95%

“…The same mechanism can be adopted for the analysis of mutation influence on the resultant stability of particular β-fragments of transthyrein [58].…”

Section: Therapymentioning

confidence: 99%

See 1 more Smart Citation

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Roterman

Banach

Kalinowska

et al. 2016

Entropy

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“…In the presence of heparin, however, the fibril formation of the 44–65 peptide was greatly enhanced, especially in the W50R variant, indicating that the inhibitory effect of the W50R mutation can be offset in the presence of heparin. Previously, it was reported that the protective effect of Lys‐35 on the amyloidogenic aggregation of transthyretin is strongly suppressed by heparin, probably through neutralization of side chain positive charges . Thus, it is plausible that the addition of a positively charged amino acid (Arg‐50) into the second amyloidogenic segment strengthens interactions with heparin, canceling out the inhibitory effect of the mutation by neutralizing positive charges.…”

Section: Discussionmentioning

confidence: 99%

Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

et al. 2016

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Glycosaminoglycans are known to be associated with extracellular amyloid deposits of various amyloidogenic proteins. In this study, we found that the glycosaminoglycan heparin greatly accelerates the elongation step in fibril formation by the N-terminal 1-83 fragment of human apolipoprotein A-I (apoA-I), especially in the amyloidogenic W50R variant. Using fragment peptides, we demonstrate that heparin significantly promotes β-transition and fibril formation of the highly amyloidogenic region spanning residues 44-65 and colocalizes with fibrils formed by the W50R variant. These results suggest the possible role of glycosaminoglycans in fibril formation by amyloidogenic apoA-I variants.

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“…It has long been recognized that in the general case of protein aggregation, and of amyloid formation in particular, hydrophobic interactions play a key role in protein condensation. In this regard, TTR aggregation is no different . Furthermore, the importance of a yet unknown network of hydrogen bonding that may be formed across dimers may also be relevant.…”

Section: Discussionmentioning

confidence: 99%

Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers

Pires

Saraiva

Damas

et al. 2016

J of Molecular Recognition

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Toxicity in amyloidogenic protein misfolding disorders is thought to involve intermediate states of aggregation associated with the formation of amyloid fibrils. Despite their relevance, the heterogeneity and transience of these oligomers have placed great barriers in our understanding of their structural properties. Among amyloid intermediates, annular oligomers or annular protofibrils have raised considerable interest because they may contribute to a mechanism of cellular toxicity via membrane permeation. Here we investigated, by using AFM force spectroscopy, the structural detail of amyloid annular oligomers from transthyretin (TTR), a protein involved in systemic and neurodegenerative amyloidogenic disorders. Manipulation was performed in situ, in the absence of molecular handles and using persistence length-fit values to select relevant curves. Force curves reveal the presence of dimers in TTR annular oligomers that unfold via a series of structural intermediates. This is in contrast with the manipulation of native TTR that was more often manipulated over length scales compatible with a TTR monomer and without unfolding intermediates. Imaging and force spectroscopy data suggest that dimers are formed by the assembly of monomers in a head-to-head orientation with a nonnative interface along their β-strands. Furthermore, these dimers stack through nonnative contacts that may enhance the stability of the misfolded structure.

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The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin

Cited by 41 publications

References 70 publications

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers

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