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Critical role of C-terminal residues of the Alzheimer's associated ?-amyloid protein in mediating antiviral activity and modulating viral and bacterial interactions with neutrophils.

ABSTRACT: Recent studies have shown that the Alzheimer's associated ?-amyloid protein (?A) can inhibit growth of bacteria, fungi and viruses. We reported that the 42 amino acid ?A protein inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro and modulates activation of neutrophils and monocytes exposed IAV. We here show that fragments composed of the N and C terminal domain of ?A42, including ?A22-42 and the 8 amino acid ?A35-42, retain viral neutralizing and viral aggregating activity, whereas fragments lacking the C-terminal amino acids 41 and 42 (e.g. ?A1-40, ?A1-34, ?A1-28, ?A22-40 or ?A33-40) have markedly diminished activities on these assays. ?A22-42 also increased viral uptake, and virus induced respiratory burst responses, by human neutrophils, while peptides lacking residues 41 and 42 did not. Similar results were obtained with regard to bacterial aggregation, or promotion of bacterial uptake by neutrophils. Published structural studies have shown that ?A1-42 has a greater propensity to form neurotoxic oligomers than ?A1-40 due to a molecular interaction between Met35 and Ala42. Our findings suggest that there is a relationship between neurotoxic and antimicrobial activities of ?A1-42. Truncated peptides containing the last 8 C-terminal amino acids of ?A1-42 retain antimicrobial and opsonizing activities likely resulting from their ability to induce viral or bacterial aggregation.

SUBMITTER: White MR

PROVIDER: S-EPMC5856391 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Critical role of C-terminal residues of the Alzheimer's associated β-amyloid protein in mediating antiviral activity and modulating viral and bacterial interactions with neutrophils.

White Mitchell R MR Kandel Ruth R Hsieh I-Ni IN De Luna Xavier X Hartshorn Kevan L KL

PloS one 20180316 3

Recent studies have shown that the Alzheimer's associated β-amyloid protein (βA) can inhibit growth of bacteria, fungi and viruses. We reported that the 42 amino acid βA protein inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro and modulates activation of neutrophils and monocytes exposed IAV. We here show that fragments composed of the N and C terminal domain of βA42, including βA22-42 and the 8 amino acid βA35-42, retain viral neutralizing ...[more]

PMID: 29547627

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Project description:Microcin E492 (MccE492) is a pore-forming bacteriocin produced and exported by Klebsiella pneumoniae RYC492. Besides its antibacterial activity, excreted MccE492 can form amyloid fibrils in vivo as well as in vitro. It has been proposed that bacterial amyloids can be functional playing a biological role, and in the particular case of MccE492 it would control the antibacterial activity. MccE492 amyloid fibril's morphology and formation kinetics in vitro have been well-characterized, however, it is not known which amino acid residues determine its amyloidogenic propensity, nor if it forms intracellular amyloid inclusions as has been reported for other bacterial amyloids. In this work we found the conditions in which MccE492 forms intracellular amyloids in Escherichia coli cells, that were visualized as round-shaped inclusion bodies recognized by two amyloidophilic probes, 2-4'-methylaminophenyl benzothiazole and thioflavin-S. We used this property to perform a flow cytometry-based assay to evaluate the aggregation propensity of MccE492 mutants, that were designed using an in silico prediction of putative aggregation hotspots. We established that the predicted amino acid residues 54-63, effectively act as a pro-amyloidogenic stretch. As in the case of other amyloidogenic proteins, this region presented two gatekeeper residues (P57 and P59), which disfavor both intracellular and in vitro MccE492 amyloid formation, preventing an uncontrolled aggregation. Mutants in each of these gatekeeper residues showed faster in vitro aggregation and bactericidal inactivation kinetics, and the two mutants were accumulated as dense amyloid inclusions in more than 80% of E. coli cells expressing these variants. In contrast, the MccE492 mutant lacking residues 54-63 showed a significantly lower intracellular aggregation propensity and slower in vitro polymerization kinetics. Electron microscopy analysis of the amyloids formed in vitro by these mutants revealed that, although with different efficiency, all formed fibrils morphologically similar to wild-type MccE492. The physiological implication of MccE492 intracellular amyloid formation is probably similar to the inactivation process observed for extracellular amyloids, and could be used as a mean of sequestering potentially toxic species inside the cell when this bacteriocin is produced in large amounts.

Dataset Information

Critical role of C-terminal residues of the Alzheimer's associated ?-amyloid protein in mediating antiviral activity and modulating viral and bacterial interactions with neutrophils.

Publications

Critical role of C-terminal residues of the Alzheimer's associated β-amyloid protein in mediating antiviral activity and modulating viral and bacterial interactions with neutrophils.

Similar Datasets

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