Solid-State NMR Studies of Amyloid Fibril Structure

Tycko, Robert

doi:10.1146/annurev-physchem-032210-103539

Cited by 513 publications

(514 citation statements)

References 118 publications

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“…The precursor proteins and peptides implicated in these diseases, regardless of the large variation in the amino acid sequences or the native structures, aggregate into amyloid fibrils that contain extensive β-sheet structures, where the β-strands are oriented perpendicular to the axis of the fibrils (Sunde and Blake 1997;Jahn et al 2010;Tycko 2011). Some precursors are mostly unstructured proteins and peptides, such as amyloid β-peptide (Aβ), amylin, and α-synuclein, while other precursors are globular proteins, such as β 2 -microglobulin (β 2 -m), lysozyme, transthyretin, and immunoglobulin.…”

Section: Introductionmentioning

confidence: 99%

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Sasahara

Goto

2012

Biophys Rev

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The aggregation of proteins into amyloid fibrils is a topic that has attracted great interest because the process is associated with the pathology of numerous human diseases. Despite considerable progress in the elucidation of the structure of amyloid fibrils and the kinetic mechanism of their formation, knowledge on the thermodynamic aspects underlying the formation and stability of amyloid fibrils is limited. In this review, we summarize recent calorimetric studies of amyloid fibril formation, with the goal of obtaining a better understanding of the causal factors that thermally induce proteins to aggregate into amyloid fibrils. Calorimetric data show that differential scanning calorimetry is a useful technique to study the causative factors that thermally trigger the conversion to the amyloid structure and highlight the physics related to the thermal fluctuation of proteins during this conversion.

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Section: Introductionmentioning

confidence: 99%

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Sasahara

Goto

2012

Biophys Rev

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“…This made NMR spectroscopy a key method for the study of protein aggregation. [6][7][8] H/D exchange coupled to solutionstate NMR spectroscopy has provided residue-specific insight into the backbone hydrogen-bonding of a variety of protein aggregates (e.g. see Refs.…”

Section: Introductionmentioning

confidence: 99%

“…Solid-state NMR spectroscopy resolved the sequence specific assignment of backbone resonances of several proteins in their amyloid state (for a review see Refs. [6][7][8]. In addition, for some amyloid fibrils intra-and intermolecular contacts were detected by solid-state NMR.…”

Section: Introductionmentioning

confidence: 99%

Determination of amyloid core structure using chemical shifts

Skora

Zweckstetter

2012

Protein Science

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Amyloid fibrils are the pathological hallmark of a large variety of neurodegenerative disorders. The structural characterization of amyloid fibrils, however, is challenging due to their non-crystalline, heterogeneous, and often dynamic nature. Thus, the structure of amyloid fibrils of many proteins is still unknown. We here show that the structure calculation program CS-Rosetta can be used to obtain insight into the core structure of amyloid fibrils. Driven by experimental solid-state NMR chemical shifts and taking into account the polymeric nature of fibrils CS-Rosetta allows modeling of the core of amyloid fibrils. Application to the Y145X stop mutant of the human prion protein reveals a left-handed b-helix.

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“…Because misfolded proteins are typically refractory to structural methods such as X-ray crystallography and solution NMR, few high-resolution structures of full-length misfolded proteins have been reported (ref. 2 and references therein). The structures of oligomeric intermediates have proven especially difficult to characterize because these conformers are labile, transient, and, in many cases, heterogeneous.…”

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confidence: 99%

Structure-based design of conformation- and sequence-specific antibodies against amyloid β

Perchiacca

Ladiwala

Bhattacharya

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

134

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Conformation-specific antibodies that recognize aggregated proteins associated with several conformational disorders (e.g., Parkinson and prion diseases) are invaluable for diagnostic and therapeutic applications. However, no systematic strategy exists for generating conformation-specific antibodies that target linear sequence epitopes within misfolded proteins. Here we report a strategy for designing conformation-and sequence-specific antibodies against misfolded proteins that is inspired by the molecular interactions governing protein aggregation. We find that grafting small amyloidogenic peptides (6-10 residues) from the Aβ42 peptide associated with Alzheimer's disease into the complementarity determining regions of a domain (V H ) antibody generates antibody variants that recognize Aβ soluble oligomers and amyloid fibrils with nanomolar affinity. We refer to these antibodies as gammabodies for grafted amyloid-motif antibodies. Gammabodies displaying the central amyloidogenic Aβ motif ( 18 VFFA 21 ) are reactive with Aβ fibrils, whereas those displaying the amyloidogenic C terminus ( 34 LMVGGVVIA 42 ) are reactive with Aβ fibrils and oligomers (and weakly reactive with Aβ monomers). Importantly, we find that the grafted motifs target the corresponding peptide segments within misfolded Aβ conformers. Aβ gammabodies fail to cross-react with other amyloidogenic proteins and scrambling their grafted sequences eliminates antibody reactivity. Finally, gammabodies that recognize Aβ soluble oligomers and fibrils also neutralize the toxicity of each Aβ conformer. We expect that our antibody design strategy is not limited to Aβ and can be used to readily generate gammabodies against other toxic misfolded proteins.misfolding | beta-amyloid | protein engineering A hallmark of protein misfolding disorders is that polypeptides of unrelated sequence fold into similar oligomeric and fibrillar assemblies that are cytotoxic (1). The structures of these enigmatic conformers have captured the imagination of many investigators who have sought to explain the molecular basis of proteotoxicity in conformational disorders such as Alzheimer's disease. Because misfolded proteins are typically refractory to structural methods such as X-ray crystallography and solution NMR, few high-resolution structures of full-length misfolded proteins have been reported (ref. 2 and references therein). The structures of oligomeric intermediates have proven especially difficult to characterize because these conformers are labile, transient, and, in many cases, heterogeneous.Given the complexity of high-resolution structural analysis of misfolded proteins, alternative biochemical approaches are critical for understanding structure-function relationships of aggregated proteins. A breakthrough in this area has been the development of conformation-specific antibodies that selectively recognize uniquely folded conformers of amyloidogenic proteins (3-13). Indeed, multiple conformation-specific antibodies have been reported that recognize structural features ...

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Solid-State NMR Studies of Amyloid Fibril Structure

Cited by 513 publications

References 118 publications

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

Determination of amyloid core structure using chemical shifts

Structure-based design of conformation- and sequence-specific antibodies against amyloid β

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