Glucagon Fibril Polymorphism Reflects Differences in Protofilament Backbone Structure

Andersen, Christian Beyschau; Hicks, Matthew R.; Vetri, Valeria; Vandahl, Brian; Rahbek-Nielsen, Henrik; Thøgersen, Henning; Thøgersen, Ida B.; Enghild, Jan J.; Serpell, Louise C.; Rischel, Christian; Otzen, Daniel E.

doi:10.1016/j.jmb.2010.02.012

Cited by 59 publications

(94 citation statements)

References 74 publications

(108 reference statements)

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“…5). LD data point to a common structural arrangement of the aromatic side chains in the weak and strong strains of Sup35 prions, which might be extended to other amyloid-prone sequences because the LD spectra of glucagon (27), β 2 -microglobulin (26), and a short sequence of the amyloid-β peptide (28) closely resemble those observed here for the Sup35 strains.…”

Section: Discussionsupporting

confidence: 64%

“…In a polymeric matrix the distribution symmetry of oriented fibers is uniaxial and therefore depends only on a single angular coordinate: angle between the fiber and the macroscopic orientation direction. Previous LD studies on amyloid samples, oriented by shear flow, are merely qualitative because the degree of alignment of the fibers could not be quantified (26)(27)(28). Without this orientation parameter it is not possible to deduce how the transition moments of chromophores are oriented in the fiber coordinate framework (Eq.…”

Section: Principles For Determining the Orientation Of Chromophores Imentioning

confidence: 99%

“…1 and Supporting Information). Additional limitations are poor fiber orientation attained by shear flow and significant increase in background scattering by the fibers, resulting in spectra of poor quality (26)(27)(28). By using a structural probe (thioflavin T, ThT) and exploiting the two different mechanisms for fiber orientation-shear-flow in the presence of sucrose and stretched polymer matrix-we attain tyrosine orientation distribution in prion fibers, which represents, to our knowledge, the first detailed, experimentally quantitative information determined by LD of the local organization of amyloids.…”

Section: Principles For Determining the Orientation Of Chromophores Imentioning

confidence: 99%

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Orientation of aromatic residues in amyloid cores: Structural insights into prion fiber diversity

Reymer

Frederick

Rocha

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Structural conversion of one given protein sequence into different amyloid states, resulting in distinct phenotypes, is one of the most intriguing phenomena of protein biology. Despite great efforts the structural origin of prion diversity remains elusive, mainly because amyloids are insoluble yet noncrystalline and therefore not easily amenable to traditional structural-biology methods. We investigate two different phenotypic prion strains, weak and strong, of yeast translation termination factor Sup35 with respect to angular orientation of tyrosines using polarized light spectroscopy. By applying a combination of alignment methods the degree of fiber orientation can be assessed, which allows a relatively accurate determination of the aromatic ring angles. Surprisingly, the strains show identical average orientations of the tyrosines, which are evenly spread through the amyloid core. Small variations between the two strains are related to the local environment of a fraction of tyrosines outside the core, potentially reflecting differences in fibril packing.linear dichroism | polarized light | prion proteins | Sup35 strains | tyrosine

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Section: Discussionsupporting

confidence: 64%

Section: Principles For Determining the Orientation Of Chromophores Imentioning

confidence: 99%

Section: Principles For Determining the Orientation Of Chromophores Imentioning

confidence: 99%

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Orientation of aromatic residues in amyloid cores: Structural insights into prion fiber diversity

Reymer

Frederick

Rocha

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Although some of this morphological diversity may emerge simply from differences in the hierarchical assembly of a single type of protofilament (9), recent research has revealed microscopic structural diversity underlying each protofilament, such as the amount of cross-␤ core, parallel/antiparallel alignment of ␤-strands, protofilament core topology, and, additionally, more minute structural variety observed at an amino acid level, as detected by using hydrogen/deuterium exchange NMR spectroscopy (10,11), solid-state NMR spectroscopy (12)(13)(14)(15), cryo-EM (16), x-ray crystallography with microcrystals (17,18), and Fourier transform infrared spectroscopy (19,20). For a comprehensive understanding and for regulation of the structure and function of each type of amyloid fibril, elucidation of the interactions inside the polypeptide chains constituting the fibrils is essential.…”

mentioning

confidence: 99%

Polymorphism of β2-Microglobulin Amyloid Fibrils Manifested by Ultrasonication-enhanced Fibril Formation in Trifluoroethanol

Chatani

Yagi

Naiki

et al. 2012

Journal of Biological Chemistry

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Background: Polymorphism of amyloid fibrils underlies the manifestation of different phenotypes of amyloidoses. Results: Various types of ␤ 2 -microglobulin fibrils were formed in 2,2,2-trifluoroethanol in a concentration-dependent manner. Conclusion:The relationship between fibril properties and TFE concentration suggests a critical role of hydrophobic interactions for polymorphism. Significance: The modulation of hydrophobic interactions will become a novel strategy for regulating amyloid diseases at a molecular level.

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“…Though there have been numerous studies of glucagon fibrillation (23)(24)(25)(26)(27)(28)(29), the molecular mechanisms involved have not been well studied, due in part to the rapid fibrillation kinetics and the lack of high-resolution methods. As with other amyloidogenic peptides and proteins, glucagon fibrillation is a complex process.…”

Section: Introductionmentioning

confidence: 99%

Structural Transitions and Interactions in the Early Stages of Human Glucagon Amyloid Fibrillation

Moorthy

Ghomi

Lill

et al. 2015

Biophysical Journal

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A mechanistic understanding of the intermolecular interactions and structural changes during fibrillation is crucial for the design of safe and efficacious glucagon formulations. Amide hydrogen/deuterium exchange with mass spectrometric analysis was used to identify the interactions and amino acids involved in the initial stages of glucagon fibril formation at acidic pH. Kinetic measurements from intrinsic and thioflavin T fluorescence showed sigmoidal behavior. Secondary structural measurement of fibrillating glucagon using far-UV circular dichroism spectroscopy showed changes in structure from random coil → α-helix → β-sheet, with increase in α-helix content during the lag phase followed by increase in β-sheet content during the growth phase. Hydrogen/deuterium exchange with mass spectrometric analysis of fibrillating glucagon suggested that C-terminal residues 22-29 are involved in interactions during the lag phase, during which N-terminal residues 1-6 showed no changes. Molecular dynamics simulations of glucagon fragments showed C-terminal to C-terminal interactions with greater α-helix content for the 20-29 fragment, with hydrophobic and aromatic residues (Phe-22, Trp-25, Val-23, and Met-27) predominantly involved. Overall, the study shows that glucagon interactions during the early phase of fibrillation are mediated through C-terminal residues, which facilitate the formation of α-helix-rich oligomers, which further undergo structural rearrangement and elongation to form β-sheet-rich mature fibrils.

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Glucagon Fibril Polymorphism Reflects Differences in Protofilament Backbone Structure

Cited by 59 publications

References 74 publications

Orientation of aromatic residues in amyloid cores: Structural insights into prion fiber diversity

Orientation of aromatic residues in amyloid cores: Structural insights into prion fiber diversity

Polymorphism of β2-Microglobulin Amyloid Fibrils Manifested by Ultrasonication-enhanced Fibril Formation in Trifluoroethanol

Structural Transitions and Interactions in the Early Stages of Human Glucagon Amyloid Fibrillation

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