Dataset Information

The peptide hormone glucagon forms amyloid fibrils with two coexisting ?-strand conformations.

ABSTRACT: Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two ?-strand conformations. The two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen bond in an antiparallel fashion along the fibril axis. Two antiparallel ?-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-?, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization could improve this important drug.

SUBMITTER: Gelenter MD

PROVIDER: S-EPMC6609468 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations.

Gelenter Martin D MD Smith Katelyn J KJ Liao Shu-Yu SY Mandala Venkata S VS Dregni Aurelio J AJ Lamm Matthew S MS Tian Yu Y Xu Wei W Pochan Darrin J DJ Tucker Thomas J TJ Su Yongchao Y Hong Mei M

Nature structural & molecular biology 20190624 7

Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthet ...[more]

PMID: 31235909

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Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

The peptide hormone glucagon forms amyloid fibrils with two coexisting ?-strand conformations.

Publications

The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations.

Similar Datasets

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