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The structures of the E22? mutant-type amyloid-? alloforms and the impact of E22? mutation on the structures of the wild-type amyloid-? alloforms.

ABSTRACT: Structural differences between the intrinsically disordered fibrillogenic wild-type A?40 and A?42 peptides are linked to Alzheimer's disease. Recently, the E22? genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22? mutant-type A?40 and A?42 alloform structures as well as the differences from the wild-type A?40 and A?42 alloform structures is currently lacking. In this study, we present the structures of the E22? mutant-type A?40 and A?42 alloforms as well as the impact of E22? mutation on the wild-type A?40 and A?42 alloform structures. For this purpose, we performed extensive microsecond-time scale parallel tempering molecular dynamics simulations coupled with thermodynamic calculations. For studying the residual secondary structure component transition stabilities, we developed and applied a new theoretical strategy in our studies. We find that the E22? mutant-type A?40 might have a higher tendency toward aggregation due to more abundant ?-sheet formation in the C-terminal region in comparison to the E22? mutant-type A?42 peptide. More abundant ?-helix is formed in the mid-domain regions of the E22? mutant-type A? alloforms rather than in their wild-type forms. The turn structure at Ala21-Ala30 of the wild-type A?, which has been linked to the aggregation process, is less abundant upon E22? mutation of both A? alloforms. Intramolecular interactions between the N-terminal and central hydrophobic core (CHC), N- and C-terminal, and CHC and C-terminal regions are less abundant or disappear in the E22? mutant-type A? alloform structures. The thermodynamic trends indicate that the wild-type A?42 tends to aggregate more than the wild-type A?40 peptide, which is in agreement with experiments. However, this trend is vice versa for the E22? mutant-type alloforms. The structural properties of the E22? mutant-type A?40 and A?42 peptides reported herein may prove useful for the development of new drugs to block the formation of toxic E22? mutant-type oligomers by either stabilizing helical or destabilizing ?-sheet structure in the C-terminal region of these two mutant alloforms.

SUBMITTER: Coskuner O

PROVIDER: S-EPMC3582298 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The structures of the E22Δ mutant-type amyloid-β alloforms and the impact of E22Δ mutation on the structures of the wild-type amyloid-β alloforms.

Coskuner Orkid O Wise-Scira Olivia O Perry George G Kitahara Taizo T

ACS chemical neuroscience 20121218 2

Structural differences between the intrinsically disordered fibrillogenic wild-type Aβ40 and Aβ42 peptides are linked to Alzheimer's disease. Recently, the E22Δ genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22Δ mutant-type Aβ40 and Aβ42 alloform structures as well as the differences from the wild-type Aβ40 and Aβ42 alloform structures is currently lacking. In this study, we present the structures of the E22 ...[more]

PMID: 23421682

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Project description:The E46K genetic missense mutation of the wild-type ?-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type ?-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type ?-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type ?-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type ?-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type ?-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in ?-sheet structure formation upon E46K mutation. In addition, the ?-sheet content of the C-terminal region increases significantly in the E46K mutant-type ?S in comparison to the wild-type ?S. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to ?-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type ?S. However, the E46K mutant-type ?S structures are less stable than the wild-type ?S. Overall, our results show that the E46K mutant-type ?S has a higher propensity to aggregate than the wild-type ?S and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant ?-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.

Project description:The A53T genetic missense mutation of the wild-type ?-synuclein (?S) protein was initially identified in Greek and Italian families with familial Parkinson's disease. Detailed understanding of the structures and the changes induced in the wild-type ?S structure by the A53T mutation, as well as establishing the direct relationships between the rapid conformational changes and free energy landscapes of these intrinsically disordered fibrillogenic proteins, helps to enhance our fundamental knowledge and to gain insights into the pathogenic mechanism of Parkinson's disease. We employed extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to determine the secondary and tertiary structural properties as well as the conformational free energy surfaces of the wild-type and A53T mutant-type ?S proteins in an aqueous solution medium using both implicit and explicit water models. The confined aqueous volume effect in the simulations of disordered proteins using an explicit model for water is addressed for a model disordered protein. We also assessed the stabilities of the residual secondary structure component interconversions in ?S based on free energy calculations at the atomic level with dynamics using our recently developed theoretical strategy. To the best of our knowledge, this study presents the first detailed comparison of the structural properties linked directly to the conformational free energy landscapes of the monomeric wild-type and A53T mutant-type ?-synuclein proteins in an aqueous solution environment. Results demonstrate that the ?-sheet structure is significantly more altered than the helical structure upon A53T mutation of the monomeric wild-type ?S protein in aqueous solution. The ?-sheet content close to the mutation site in the N-terminal region is more abundant while the non-amyloid-? component (NAC) and C-terminal regions show a decrease in ?-sheet abundance upon A53T mutation. Obtained results utilizing our new theoretical strategy show that the residual secondary structure conversion stabilities resulting in ?-helix formation are not significantly affected by the mutation. Interestingly, the residual secondary structure conversion stabilities show that secondary structure conversions resulting in ?-sheet formation are influenced by the A53T mutation and the most stable residual transition yielding ?-sheet occurs directly from the coil structure. Long-range interactions detected between the NAC region and the N- or C-terminal regions of the wild-type ?S disappear upon A53T mutation. The A53T mutant-type ?S structures are thermodynamically more stable than those of the wild-type ?S protein structures in aqueous solution. Overall, the higher propensity of the A53T mutant-type ?S protein to aggregate in comparison to the wild-type ?S protein is related to the increased ?-sheet formation and lack of strong intramolecular long-range interactions in the N-terminal region in comparison to its wild-type form. The specific residual secondary structure component stabilities reported herein provide information helpful for designing and synthesizing small organic molecules that can block the ?-sheet forming residues, which are reactive toward aggregation.

Project description:The ?E693 (Japanese) mutation of the ?-amyloid precursor protein leads to production of ?E22-A? peptides such as ?E22-A?(1-39). Despite reports that these peptides do not form fibrils, here we show that, on the contrary, the peptide forms fibrils essentially instantaneously. The fibrils are typical amyloid fibrils in all respects except that they cause only low levels of thioflavin T (ThT) fluorescence, which, however, develops with no lag phase. The fibrils bind ThT, but with a lower affinity and a smaller number of binding sites than wild-type (WT) A?(1-40). Fluorescence depolarization confirms extremely rapid aggregation of ?E22-A?(1-39). Size exclusion chromatography (SEC) indicates very low concentrations of soluble monomer and oligomer, but only in the presence of some organic solvent, e.g., 2% (v/v) DMSO. The critical concentration is approximately 1 order of magnitude lower for ?E22-A?(1-39) than for WT A?(1-40). Several lines of evidence point to an altered structure for ?E22-A?(1-39) compared to that of WT A?(1-40) fibrils. In addition to differences in ThT binding and fluorescence, PITHIRDS-CT solid-state nuclear magnetic resonance (NMR) measurements of ?E22-A?(1-39) are not compatible with the parallel in-register ?-sheet generally observed for WT A?(1-40) fibrils. X-ray fibril diffraction showed different D spacings: 4.7 and 10.4 Å for WT A?(1-40) and 4.7 and 9.6 Å for ?E22-A?(1-39). Equimolar mixtures of ?E22-A?(1-39) and WT A?(1-40) also produced fibrils extremely rapidly, and by the criteria of ThT fluorescence and electron microscopic appearance, they were the same as fibrils made from pure ?E22-A?(1-39). X-ray diffraction of fibrils formed from 1:1 molar mixtures of ?E22-A?(1-39) and WT A?(1-40) showed the same D spacings as fibrils of the pure mutant peptide, not the wild-type peptide. These findings are consistent with extremely rapid nucleation by ?E22-A?(1-39), followed by fibril extension by WT A?(1-40), and "conversion" of the wild-type peptide to a structure similar to that of the mutant peptide, in a manner reminiscent of the prion conversion phenomenon.

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Dataset Information

The structures of the E22? mutant-type amyloid-? alloforms and the impact of E22? mutation on the structures of the wild-type amyloid-? alloforms.

Publications

The structures of the E22Δ mutant-type amyloid-β alloforms and the impact of E22Δ mutation on the structures of the wild-type amyloid-β alloforms.

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