Probing Solvent Accessibility of Transthyretin Amyloid by Solution NMR Spectroscopy

Olofsson, Anders; Ippel, Hans; Wijmenga, Sybren S.; Lundgren, Erik; Öhman, Anders

doi:10.1074/jbc.m310605200

Cited by 106 publications

(126 citation statements)

References 39 publications

(78 reference statements)

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“…To test the idea that strands C and D must be displaced from the TTR monomer b-sandwich for amyloid formation to occur, [12][13][14][15][16][17] we have also inspected the variation of SASA for the side-chains belonging to residues in strands A and B, against that of the side-chains of all other residues in the TTR monomer (Fig. 4).…”

Section: Analysis Of Global Structural Propertiesmentioning

confidence: 99%

“…We have previously published a molecular model of a TTR protofilament 17 based on experimental constraints obtained by EPR and NMR. 15,16 To build a model having the continuous extended cross-b structure characteristic of amyloid, 12 full displacement of strands C and D from the TTR b-sandwich was required to expose a new interface formed by strands A and B, and allow monomer to monomer docking. 17 The positioning of strands C and D and exposure of strands A and B were followed by analysis of the variation of SASA along the MD simulation trajectories.…”

Section: Insights On the Exposure Of B-strands A And Bmentioning

confidence: 99%

“…1) from its native position is believed to be essential in order to expose a new interface comprised by strands A and B, necessary for monomer assembly into aggregates. [12][13][14] Site-directed spin labeling combined with electron paramagnetic resonance (EPR) 15 and hydrogen/deuterium (H/D) exchange studies by nuclear magnetic resonance (NMR) spectroscopy have supported this hypothesis 16 and, recently, a computational model of an amyloid protofilament of TTR was proposed 17 where proper subunit-subunit docking was only achieved if the D-strand-loop-C-strand segment was fully displaced from the b-sandwich core of the TTR subunit.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Analysis Of Global Structural Propertiesmentioning

confidence: 99%

Section: Insights On the Exposure Of B-strands A And Bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…The determination of detailed structures of the mature fibrils is also challenging due to their intractable and frequently heterogeneous nature, which again seriously limits the application of the traditional methods of structural biology such as solution NMR spectroscopy and X-ray diffraction techniques. Structural information concerning amyloid fibrils has, however, been obtained from atomic force microscopy (AFM) [30,31], FTIR [32,33], X-ray fibre diffraction studies [17], cryoelectron microscopy [34,35], hydrogen/deuterium exchange analysed by mass spectrometry and NMR [36][37][38][39] and solid state NMR [40,41]. Important information about both the structures of the aggregates and the mechanism of their formation has also been obtained by using methods such as limited proteolysis [42,43], systematic site-directed mutagenesis [44][45][46], and the analysis of the effects of interactions with specific antibodies.…”

Section: The Generic Nature Of the Amyloid Structurementioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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“…This partial misfolding mechanism was supported later by a search for structural determinants of the amyloidogenic fold (17), in which two monoclonal antibodies bind specifically to regions comprising residues 39-44 (in the C strand) and 56-61 (after the D strand) only when the C and D strands adopt a non-native conformation. Further evidence lies in the investigations of fibril structure (18)(19)(20), suggesting that the A, B, and E-H strands retain their nativelike conformation and constitute the fibril core with the C strandloop-D strand region protruding from the core. The subunit interface in the fibril state is formed between strands A and A′, B and B′, F and F′, and H and H′ with a possible shift in register between the two F strands and H strands.…”

mentioning

confidence: 99%

The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

et al. 2006

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Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.

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Probing Solvent Accessibility of Transthyretin Amyloid by Solution NMR Spectroscopy

Cited by 106 publications

References 39 publications

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

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

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

The Sequence-Dependent Unfolding Pathway Plays a Critical Role in the Amyloidogenicity of Transthyretin

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