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A common pathway for detergent-assisted oligomerization of Aβ42.

ABSTRACT: Amyloid beta (Aβ) aggregation is a slow process without seeding or assisted nucleation. Sodium dodecyl sulfate (SDS) micelles stabilize Aβ42 small oligomers (in the dimer to tetramer range); subsequent SDS removal leads to a 150-kD Aβ42 oligomer. Dodecylphosphorylcholine (DPC) micelles also stabilize an Aβ42 tetramer. Here we investigate the detergent-assisted oligomerization pathway by solid-state NMR spectroscopy and molecular dynamics simulations. SDS- and DPC-induced oligomers have the same structure, implying a common oligomerization pathway. An antiparallel β-sheet formed by the C-terminal region, the only stable structure in SDS and DPC micelles, is directly incorporated into the 150-kD oligomer. Three Gly residues (at positions 33, 37, and 38) create holes that are filled by the SDS and DPC hydrocarbon tails, thereby turning a potentially destabilizing feature into a stabilizing factor. These observations have implications for endogenous Aβ aggregation at cellular interfaces.

SUBMITTER: Muhammedkutty FNK

PROVIDER: S-EPMC10663524 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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A common pathway for detergent-assisted oligomerization of Aβ42.

Muhammedkutty Fidha Nazreen Kunnath FNK Prasad Ramesh R Gao Yuan Y Sudarshan Tarunya Rao TR Robang Alicia S AS Watzlawik Jens O JO Rosenberry Terrone L TL Paravastu Anant K AK Zhou Huan-Xiang HX

Communications biology 20231121 1

Amyloid beta (Aβ) aggregation is a slow process without seeding or assisted nucleation. Sodium dodecyl sulfate (SDS) micelles stabilize Aβ42 small oligomers (in the dimer to tetramer range); subsequent SDS removal leads to a 150-kD Aβ42 oligomer. Dodecylphosphorylcholine (DPC) micelles also stabilize an Aβ42 tetramer. Here we investigate the detergent-assisted oligomerization pathway by solid-state NMR spectroscopy and molecular dynamics simulations. SDS- and DPC-induced oligomers have the same ...[more]

PMID: 37989804

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Project description:Aquaporins are tetrameric integral membrane proteins that act as water channels, and can also permeabilize membranes to other solutes. The monomer appears to be the functional form despite all aquaporins being organized as tetramers, which therefore must provide a clear functional advantage. In addition to this quaternary organization, some aquaporins can act as adhesion molecules in membrane junctions, when tetramers located in opposing membranes interact via their extracellular domains. These stacked forms have been observed in a range of aquaporins, whether using lipidic membrane environments, in electron crystallography, or using detergent micelles, in single-particle cryo-electron microscopy (cryo-EM). In the latter technique, structural studies can be performed when the aquaporin is reconstituted into nanodiscs of lipids that are surrounded by a protein scaffold. During attempts to study E. coli Aquaporin Z (AqpZ), we have found that in some conditions these nanodiscs tend to form filaments that appear to be either thicker head-to-tail or thinner side-to-side stacks of nanodiscs. Nanodisc oligomerization was observed using orthogonal analytical techniques analytical ultra-centrifugation and mass photometry, although the nature of the oligomers (head-to-tail or side-to-side) could not be determined. Using the latter technique, the AqpZ tetramer itself formed oligomers of increasing size when solubilized only in detergent, which is consistent with multiple stacking of AqpZ tetramers. We observed images consistent with both of these filaments in negative staining EM conditions, but only thicker filaments in cryo-EM conditions. We hypothesize that the apparent nanodisc side-to-side arrangement that can only be visualized in negative staining conditions is related to artifacts due to the sample preparation. Filaments of any kind were not observed in EM when nanodiscs did not contain AqpZ, or after addition of detergent into the nanodisc cryo-EM preparation, at concentrations that did not disrupt nanodisc formation. To our knowledge, these filaments have not been observed in nanodiscs preparations of other membrane proteins. AqpZ, like other aquaporins has a charge asymmetry between the cytoplasmic (more positive) and the extracellular sides, which may explain the likely head-to-tail stacking observed, both in nanodisc preparations and also in detergent micelles.

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A common pathway for detergent-assisted oligomerization of Aβ42.

Publications

A common pathway for detergent-assisted oligomerization of Aβ42.

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