Dataset Information

Supramolecular Bait to Trigger Non-Equilibrium Co-Assembly and Clearance of A?42.

ABSTRACT: In living systems, non-equilibrium states that control the assembly-disassembly of cellular components underlie the gradual complexification of life, whereas in nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. Little is known about the roles of non-equilibrium states of interactions between supramolecules in living systems. Here, a non-equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and A?42, an aggregate-prone protein that causes Alzheimer's disease (AD), was identified. Structurally, A?42 presents a specific groove that is recognized by the amphiphilicity of LPS bait in a non-equilibrium manner. Functionally, the transient complex elicits a cellular response to clear extracellular A?42 deposits in neuronal cells. Since the impaired clearance of toxic A?42 deposits correlates with AD pathology, the non-equilibrium LPS and A?42 could represent a useful target for developing AD therapeutics.

SUBMITTER: Wu TH

PROVIDER: S-EPMC7898541 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Supramolecular Bait to Trigger Non-Equilibrium Co-Assembly and Clearance of Aβ42.

Wu Te-Haw TH Lai Rai-Hua RH Yao Chun-Nien CN Juang Jyh-Lyh JL Lin Shu-Yi SY

Angewandte Chemie (International ed. in English) 20201227 8

In living systems, non-equilibrium states that control the assembly-disassembly of cellular components underlie the gradual complexification of life, whereas in nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. Little is known about the roles of non-equilibrium states of interactions between supramolecules in living systems. Here, a non-equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggreg ...[more]

PMID: 33191624

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Project description:Supramolecular assembly of biomolecules/macromolecules stems from the desire to mimic complex biological structures and functions of living organisms. While DNA nanotechnology is already in an advanced stage, protein assembly is still in its infancy as it is a significantly difficult task due to their large molecular weight, conformational complexity and structural instability towards variation in temperature, pH or ionic strength. This article reports highly stable redox-responsive supramolecular assembly of a protein Bovine serum albumin (BSA) which is functionalized with a supramolecular structure directing unit (SSDU). The SSDU consists of a benzamide functionalized naphthalene-diimide (NDI) chromophore which is attached with the protein by a bio-reducible disulfide linker. The SSDU attached protein (NDI-BSA) exhibits spontaneous supramolecular assembly in water by off-set π-stacking among the NDI chromophores, leading to the formation of spherical nanoparticles (diameter: 150-200 nm). The same SSDU when connected with a small hydrophilic wedge (NDI-1) instead of the large globular protein, exhibits a different π-stacking mode with relatively less longitudinal displacement which results in a fibrillar network and hydrogelation. Supramolecular co-assembly of NDI-BSA and NDI-1 (3 : 7) produces similar π-stacking and an entangled 1D morphology. Both the spherical assembly of NDI-BSA or the fibrillar co-assembly of NDI-BSA + NDI-1 (3 : 7) provide sufficient thermal stability to the protein as its thermal denaturation could be completely surpassed while the secondary structure remained intact. However, the esterase like activity of the protein reduced significantly as a result of such supramolecular assembly indicating limited access by the substrate to the active site of the enzyme located in the confined environment. In the presence of glutathione (GSH), a biologically important tri-peptide, due to the cleavage of the disulfide bond, the protein became free and was released, resulting in fully regaining its enzymatic activity. Such supramolecular assembly provided excellent protection to the protein against enzymatic hydrolysis as the relative hydrolysis was estimated to be <30% for the co-assembled protein with respect to the free protein under identical conditions. Similar to bioactivity, the enzymatic hydrolysis also became prominent after GSH-treatment, confirming that the lack of hydrolysis in the supramolecularly assembled state is indeed related to the confinement of the protein in the nanostructure assembly.

Dataset Information

Supramolecular Bait to Trigger Non-Equilibrium Co-Assembly and Clearance of A?42.

Publications

Supramolecular Bait to Trigger Non-Equilibrium Co-Assembly and Clearance of Aβ42.

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