Structure determination of micelle-like intermediates in amyloid β-protein fibril assembly by using small angle neutron scattering

Yong, W.; Lomakin, Aleksey; Kirkitadze, Marina; Teplow, David B.; Chen, Sow‐Hsin; Benedek, George B.

doi:10.1073/pnas.012584899

Cited by 179 publications

(167 citation statements)

References 18 publications

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“…As the radial density goes to zero between 2 and 3 nm, we can estimate that the pentamers are of an average diameter 5 Ϯ 1 nm. This result agrees well with the diameter of micelle-like intermediates and͞or stable globular oligomers as experimentally determined by small-angle neutron scattering (42) and atomic force microscopy (43).…”

Section: Time Evolution Of Contacts and Secondary Structure During A␤supporting

confidence: 80%

In silico study of amyloid β-protein folding and oligomerization

Urbanc

Cruz

Yun

et al. 2004

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

330

478

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Experimental findings suggest that oligomeric forms of the amyloid ␤ protein (A␤) play a critical role in Alzheimer's disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, A␤40 and A␤42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. A␤40 forms significantly more dimers than A␤42, whereas pentamers are significantly more abundant in A␤42 relative to A␤40. Structure analysis reveals a turn centered at Gly-37-Gly-38 that is present in a folded A␤42 monomer but not in a folded A␤40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in A␤42 pentamer formation. A␤ pentamers have a globular structure comprising hydrophobic residues within the pentamer's core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of A␤40 pentamers are more spatially restricted than A␤42 pentamers. A␤40 pentamers form a ␤-strand structure involving Ala-2-Phe-4, which is absent in A␤42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the A␤42 pentamer being more exposed and thus more prone to form larger oligomers.Alzheimer's disease ͉ discrete molecular dynamics ͉ four-bead protein model ͉ oligomer formation T he amyloid ␤-protein (A␤) has been strongly linked to the etiology and pathogenesis of Alzheimer's disease (AD). A␤ assembles into amyloid fibrils and smaller, oligomeric assemblies. Experimental and clinical findings suggest that protofibrillar intermediates (1-3) and oligomeric forms (4-13) of A␤ may be particularly important. If so, elucidating the structures of these A␤ oligomers and the mechanisms of their formation is critical for developing therapeutic agents. Unlike proteins with stable folds, A␤ oligomers are metastable. They cannot be crystallized for x-ray diffraction studies nor can they be easily studied by using solutionphase NMR. Monomers and oligomers are also in dynamic equilibrium, which makes the study of pure populations of conformers using classical biophysical techniques difficult.A␤ exists in two predominant forms, 40 (A␤40) or 42 (A␤42) amino acids in length. Of the two, A␤42 is associated most strongly with an increased risk for AD, is more neurotoxic, and forms fibrils significantly faster. Recent experiments demonstrated that A␤ oligomers can be covalently cross-linked, and therefore stabilized, by using the technique of photo-induced cross-linking of unmodified proteins (PICUP) (14). During PICUP coupled with si...

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Section: Time Evolution Of Contacts and Secondary Structure During A␤supporting

confidence: 80%

In silico study of amyloid β-protein folding and oligomerization

Urbanc

Cruz

Yun

et al. 2004

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

330

478

View full text Add to dashboard Cite

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“…Circumstantial evidence for this can be found in the existence of intermediates of various nonfibrillar morphologies (9)(10)(11)(12)(13)(14)37). From a kinetic point of view, they occur because they are easier to form, not because they are energetically more stable.…”

Section: Origin Of the Preference For Left-facing Configurationsmentioning

confidence: 98%

“…Amyloid fibrillogenesis is a multistage process (7,8) with a variety of intermediate structures, appearing in different fiberforming systems; they include ␣-helices (9), globules (10,11), toroids (12,13), and helical ribbons (14). Some of these small oligomeric aggregates have been suggested to be the cytotoxic species in certain neurodegenerative diseases (15,16).…”

mentioning

confidence: 99%

Kinetic control of dimer structure formation in amyloid fibrillogenesis

Hwang

Zhang

Kamm

et al. 2004

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

179

266

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Amyloid fibril formation involves nonfibrillar oligomeric intermediates, which are important as possible cytotoxic species in neurodegenerative diseases. However, their transient nature and polydispersity have made it difficult to identify their formation mechanism or structure. We have investigated the dimerization process, the first step in aggregate formation, by multiple molecular dynamics simulations of five ␤-sheet-forming peptides. Contrary to the regular ␤-sheet structure of the amyloid fibril, the dimers exhibit all possible combinations of ␤-sheets, with an overall preference for antiparallel arrangements. Through statistical analysis of 1,000 dimerization trajectories, each 1 ns in length, we have demonstrated that the observed distribution of dimer configurations is kinetically determined; hydrophobic interactions orient the peptides so as to minimize the solvent accessible surface area, and the dimer structures become trapped in energetically unfavorable conformations. Once the hydrophobic contacts are present, the backbone hydrogen bonds form rapidly by a zipper-like mechanism. The initial nonequilibrium structures formed are stable during the 1-ns simulation time for all five peptides at room temperature. In contrast, at higher temperatures, where rapid equilibration among different configurations occurs, the distribution follows the global energies. The relaxation time of dimers at room temperature was estimated to be longer than the time for diffusional encounters with other oligomers at typical concentrations. These results suggest that kinetic trapping could play a role in the structural evolution of early aggregates in amyloid fibrillogenesis.

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“…A subset of proteins within this ensemble will undergo non-ordered aggregation to form nuclei. When viewed by transmission electron (TEM) or atomic-force (AFM) microscopy, these species may appear as small beads that are linked together to produce what are often described as amorphous aggregates or micelles (Yong et al, 2002). The nucleation phase, which constitutes the rate-limiting step in amyloid formation, is relatively slow, due largely to unfavourable protein association equilibria rather than to intrinsically slow association rates (Jarrett and Lansbury 1993).…”

Section: Amyloid Formationmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Structure determination of micelle-like intermediates in amyloid β-protein fibril assembly by using small angle neutron scattering

Cited by 179 publications

References 18 publications

In silico study of amyloid β-protein folding and oligomerization

In silico study of amyloid β-protein folding and oligomerization

Kinetic control of dimer structure formation in amyloid fibrillogenesis

Extracellular Chaperones and Amyloids

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