| 1. |
- Liu, Chang, et al.
(författare)
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Oligomer Dynamics of LL-37 Truncated Fragments Probed by α-Hemolysin Pore and Molecular Simulations
- 2023
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Ingår i: Small. - 1613-6810 .- 1613-6829. ; 19:37
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Tidskriftsartikel (refereegranskat)abstract
- Oligomerization of antimicrobial peptides (AMPs) is critical in their effects on pathogens. LL-37 and its truncated fragments are widely investigated regarding their structures, antimicrobial activities, and application, such as developing new antibiotics. Due to the small size and weak intermolecular interactions of LL-37 fragments, it is still elusive to establish the relationship between oligomeric states and antimicrobial activities. Here, an α-hemolysin nanopore, mass spectrometry (MS), and molecular dynamic (MD) simulations are used to characterize the oligomeric states of two LL-37 fragments. Nanopore studies provide evidence of trapping events related to the oligomer formation and provide further details on their stabilities, which are confirmed by MS and MD simulations. Furthermore, simulation results reveal the molecular basis of oligomer dynamics and states of LL-37 fragments. This work provides unique insights into the relationship between the oligomer dynamics of AMPs and their antimicrobial activities at the single-molecule level. The study demonstrates how integrating methods allows deciphering single molecule level understanding from nanopore sensing approaches.
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| 2. |
- Loch, Rolf Antonie, et al.
(författare)
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Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases
- 2023
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 21, s. 1189-1204
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Tidskriftsartikel (refereegranskat)abstract
- Three common Apolipoprotein E isoforms, ApoE2, ApoE3, and ApoE4, are key regulators of lipid homeostasis, among other functions. Apolipoprotein E can interact with amyloid proteins. The isoforms differ by one or two residues at positions 112 and 158, and possess distinct structural conformations and functions, leading to isoform-specific roles in amyloid-based neurodegenerative diseases. Over 30 different amyloid proteins have been found to share similar characteristics of structure and toxicity, suggesting a common interactome. The molecular and genetic interactions of ApoE with amyloid proteins have been extensively studied in neurodegenerative diseases, but have not yet been well connected and clarified. Here we summarize essential features of the interactions between ApoE and different amyloid proteins, identify gaps in the understanding of the interactome and propose the general interaction mechanism between ApoE isoforms and amyloid proteins. Perhaps more importantly, this review outlines what we can learn from the interactome of ApoE and amyloid proteins; that is the need to see both ApoE and amyloid proteins as a basis to understand neurodegenerative diseases.
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| 3. |
- Wang, Hongzhi, et al.
(författare)
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ATP Impedes the Inhibitory Effect of Hsp90 on Aβ(40) Fibrillation
- 2021
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 433:2
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Tidskriftsartikel (refereegranskat)abstract
- Heat shock protein 90 (Hsp90) is a molecular chaperone that assists protein folding in an Adenosine triphosphate (ATP)-dependent way. Hsp90 has been reported to interact with Alzheimer's disease associated amyloid-beta (A beta) peptides and to suppress toxic oligomer- and fibril formation. However, the mechanism remains largely unclear. Here we use a combination of atomic force microscopy (AFM) imaging, circular dichroism (CD) spectroscopy and biochemical analysis to quantify this interaction and put forward a microscopic picture including rate constants for the different transitions towards fibrillation. We show that Hsp90 binds to A beta(40) monomers weakly but inhibits A beta(40) from growing into fibrils at substoichiometric concentrations. ATP impedes this interaction, presumably by modulating Hsp90's conformational dynamics and reducing its hydrophobic surface. Altogether, these results might indicate alternative ways to prevent A beta(40) fibrillation by manipulating chaperones that are already abundant in the brain.
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| 4. |
- Wu, Jinming, et al.
(författare)
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Identifying the role of co-aggregation of Alzheimer's amyloid-beta with amorphous protein aggregates of non-amyloid proteins
- 2022
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Ingår i: Cell Reports Physical Science. - : Elsevier BV. - 2666-3864. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- Protein homeostasis collapse typically leads to protein aggregation into amyloid fibrils and diffuse amorphous aggregates, which both occur in Alzheimer’s and other neurodegenerative diseases, but their relationship remains to be clarified. Here we examine the interactions between the amorphously aggregated non-chaperone proteins (albumin, β-lactoglobulin, and superoxide dismutase 1) and Alzheimer’s amyloid-β (Aβ) peptides. Amorphous aggregates suppress the primary nucleation and elongation of Aβ fibrillation and modulate Aβ toxicity. The higher inhibitory efficiency of intermediately sized molten globular aggregates (20–300 nm) on Aβ fibrillation is hypothesized to be due to the higher amount of exposed hydrophobic residues and higher free energy. The formed co-aggregates are off-pathway species that favor formation of the amorphous end state instead of fibrillar amyloid structures normally formed by Aβ. Our findings expand our knowledge of how the native and aggregated cellular proteins modulate Aβ aggregation at the molecular and mesoscopic level and point out the major conclusions.
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