Membrane-Induced Dichotomous Conformation of Amyloid β with the Disordered N-Terminal Segment Followed by the Stable C-Terminal β Structure

Yagi-Utsumi, Maho; Kato, Koichi; Nishimura, Katsuyuki

doi:10.1371/journal.pone.0146405

Cited by 19 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The A β peptide has 40–43 amino acid residues, and assembles into amyloid fibrils with a cross- β structure comprising two β -sheets, β 1 and β 2, as shown in Fig. 1(a) 567. The A β peptides arrange in an orderly array with the same confirmation along the amyloid fibril axis.…”

mentioning

confidence: 99%

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Okumura

Itoh

2016

Sci Rep

View full text Add to dashboard Cite

Aβ amyloid fibrils, which are related to Alzheimer’s disease, have a cross-β structure consisting of two β-sheets: β1 and β2. The Aβ peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Aβ42 and Aβ40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Aβ peptide always took a closed form wherein β1 and β2 were closely spaced. The Aβ peptide fluctuated more at the odd end and took an open form wherein the two β-sheets were well separated. The differences are attributed to the stronger β-sheet formation by the β1 exposed at the even end than the β2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy.

show abstract

mentioning

confidence: 99%

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Okumura

Itoh

2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…46) Furthermore, our solution NMR data suggest that Aβ adopts a β-structure at higher densities on the clusters of GM1, whereas an α-to-β conformational transition on 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayers was revealed by our solid-state NMR measurements. 47,48) These findings demonstrate that the interaction between Aβ(1-40) and GM1 clusters involves multiple steps, including accommodation, conformational transition, and subsequent oligomerization processes. Namely, the GM1 cluster provides a unique platform at its hydrophobic/hydrophilic interface for binding coupled with the α-helix formation of Aβ molecules.…”

Section: Biographymentioning

confidence: 80%

NMR Characterization of Conformational Dynamics and Molecular Assemblies of Proteins

Yagi-Utsumi

2019

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Dynamic conformational transitions and molecular assemblies are essential properties of proteins, and relevant to their biological and pathological functions. Neurodegenerative diseases are known to be caused by abnormal, toxic assemblies of related proteins, e.g., amyloid β (Aβ) in Alzheimer's disease. Growing evidence indicates that the aggregation of various amyloidogenic proteins, including Aβ, can be highly enhanced at glycolipid membranes, suggesting that dynamic glycolipid-dependent conformational changes of proteins constitute crucial steps for their subsequent pathogenic amyloid fibril formation. It has also been proposed that several proteins, including molecular chaperones, can capture amyloidogenic proteins and thereby suppress their fibrillization. NMR spectroscopy provides a powerful tool for characterizing the conformational dynamics and intermolecular interactions of proteins, as well as for exploring transiently formed weak interactions among proteins in solution with various biomolecules, such as glycolipids. Our research group therefore attempted to elucidate the structural basis of protein-glycolipid and protein-protein interactions that either promote or suppress molecular assemblies of amyloidogenic proteins, using both solution and solid-state NMR methods in conjunction with other biophysical techniques. Our findings provide structural views of molecular processes involving amyloidogenic proteins of clinical and pathological interest and offer clues for the development of drugs to prevent and treat neurodegenerative diseases.

show abstract

“…Elements of the E11-E22 and C-terminal segments are expected to adopt the C 7eq fold while the array of consecutive ‘turns’ D23-M35 may be stabilized as the ‘C 5 * strand’; in contrast, the E3-D7 segment may adopt a helical conformation. The G25-V39 segment of Aβ 1–40 bound to DMPC bilayer (multilamella vesicles composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine, high P/L ratio) is indeed reported to fold into a parallel β structure [ 176 , 177 ]. On the other hand, the E3-D7 residues buried in the CDR loops of the complexes with monoclonal antibodies are found to be helical: PP II - (PDB ID’s 2ipu, 3bae) or 3 10 - (PDB ID 4hix) [ 178 ].…”

Section: Resultsmentioning

confidence: 99%

“…The expected conformational transition is well documented, cf. Fig 22A(a) and 22A(b) [ 176 , 177 , 181 – 184 ], and may well contribute to the catalysis of polymerization by membranes and lipid rafts [ 247 – 254 ].…”

Section: Resultsmentioning

confidence: 99%

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

Cieplak

2017

PLoS ONE

View full text Add to dashboard Cite

Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates’ morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer’s and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer’s amyloid β and tau, Parkinson’s α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aβ, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions.

show abstract

Membrane-Induced Dichotomous Conformation of Amyloid β with the Disordered N-Terminal Segment Followed by the Stable C-Terminal β Structure

Cited by 19 publications

References 41 publications

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

NMR Characterization of Conformational Dynamics and Molecular Assemblies of Proteins

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

Contact Info

Product

Resources

About