Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP

Maj, Michał; Lomont, Justin P.; Rich, Kacie L.; Alperstein, Ariel M.; Zanni, Martin T.

doi:10.1039/c7sc03789a

Cited by 40 publications

(74 citation statements)

References 81 publications

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“…Helices were centered around residues 10–15, displaying a high helical propensity over 0.65 when the number of simulated peptides was less than eight. This result is consistent with a recent 2D infrared spectroscopy (2D IR) study, where residues L12A13 mainly adopted the helical structure, but residues L16V17 did not in the monomeric state . As the number of peptides increased to ten and more, the average helical probability for above residues decreased to around 0.5.…”

Section: Resultssupporting

confidence: 92%

“…Replica exchange MD simulations combined with IMS‐MS experiments demonstrated the intrinsic propensity of hIAPP monomers to form β‐hairpin conformations, which could take place in the oligomers. Depending on experimental conditions of aggregation such as concentrations and the presence of co‐solvents or membranes, the appearance of helical intermediates may vary but the formation of β‐sheet‐rich oligomers should be the obligatory step toward amyloid aggregation. Hence, our study of hIAPP8‐20 aggregation sheds a new light on the aggregation of full‐length hIAPP.…”

Section: Resultsmentioning

confidence: 99%

“…De Carufel et al found that preventing helical folding with nonhelical hIAPP analogs increased hIAPP cytotoxicity, indicating the cytotoxicity of hIAPP might be irrelevant of helical intermediates. In addition, Maj et al reported that helices in hIAPP could seed oligomer formation but were not necessary for amyloid formation . Hence, the exact role of these helical intermediates in the hIAPP aggregation and the associated amyloid cytotoxicity remains still unclear, and so does the conversion of these helical structures to final β‐sheets.…”

Section: Introductionmentioning

confidence: 99%

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Amyloid Self‐Assembly of hIAPP8‐20 via the Accumulation of Helical Oligomers, α‐Helix to β‐Sheet Transition, and Formation of β‐Barrel Intermediates

Sun

Käkinen

Xing

et al. 2019

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The self-assembly of peptides has attracted a great attention due to its association with numerous degenerative diseases (e.g., Alzheimer's, [1] Parkinson's, [1] and type II diabetes [2] ) and itsThe self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheetrich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8-17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8-20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nanofibrils in silico from isolated helical monomers via the helical oligomers and α-helices to β-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the α-to-β transition starts from the hexamers. Converted β-sheet-rich oligomers first form β-barrel structures as intermediates before aggregating into cross-β nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amyloid Self‐Assembly of hIAPP8‐20 via the Accumulation of Helical Oligomers, α‐Helix to β‐Sheet Transition, and Formation of β‐Barrel Intermediates

Sun

Käkinen

Xing

et al. 2019

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“…Short ThT-positive fibrils were even observable immediately after solubilization of N21n. Previous studies have suggested that the segment 20 -29 mediates initial self-recognition and that early oligomers contain stacks of parallel ␤-sheet within the 23 FGAIL 27 region (24,49,50). However, below a critical concentration, IAPP self-recognition appears to be primarily initiated by the N-terminal region, which than propagates to the central domain (51).…”

Section: Self-assembly-toxicity Relationships Of Iappmentioning

confidence: 97%

“…In contrast, by using a helix-disrupting analog, it has been proposed that helical species are off-pathway and that preventing helical folding increases cytotoxicity (23). Moreover, it has been reported that helical conformations are mainly found in the monomeric state and could seed oligomer formation, although they are not mandatory for amyloid growth (24).…”

mentioning

confidence: 99%

Identification of a hinge residue controlling islet amyloid polypeptide self-assembly and cytotoxicity

Godin

Nguyen

Zottig

et al. 2019

Journal of Biological Chemistry

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The islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone whose deposition as amyloid fibrils in the pancreatic islets is associated with type 2 diabetes. Previous studies have suggested that residue Asn-21 plays a critical role in the in vitro self-assembly of IAPP. Herein, we studied structure-self-assembly relationships focusing on position 21 to gain detailed insights into the molecular mechanisms of IAPP self-assembly and to probe the conformational nature of the toxic assemblies associated with ␤-cell death. Thioflavin T (ThT) fluorescence, CD spectroscopy, and transmission EM analysis revealed that the Asn-21 amide side chain is not required for IAPP nucleation and amyloid elongation, as N21A and N21G variants assembled into prototypical fibrils. In contrast, Asn-21 substitution with the conformationally constrained and turn-inducing residue Pro accelerated IAPP self-assembly. Successive substitutions with hydrophobic residues led to the formation of ThT-negative ␤-sheet-rich aggregates having high surface hydrophobicity. Cell-based assays revealed no direct correlation between the in vitro amyloidogenicity of these variants and their toxicity. In contrast, leakage of anionic lipid vesicles disclosed that membrane disruption is closely associated with cytotoxicity. We observed that the N21F variant self-assembles into worm-like aggregates, causing loss of lipid membrane structural integrity and inducing ␤-cell apoptosis. These results indicate that specific intra-and intermolecular interactions involving Asn-21 promote IAPP primary nucleation events by modulating the conformational conversion of the oligomeric intermediates into amyloid fibrils. Our study identifies position 21 as a hinge residue that modulates IAPP amyloidogenicity and cytotoxicity.

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Introduction to State-of-the-Art Multidimensional Time-Resolved Spectroscopy Methods

Kraack

Buckup

2018

Top Curr Chem (Z)

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The field of multidimensional laser spectroscopy comprises a variety of highly developed state-of-the-art methods, which exhibit broad prospects for applications in several areas of natural, material, and even medical sciences. This collection summarizes the main achievements from this area and gives basic introductory insight into what is currently possible with such methods. In the present introductory contribution, we briefly outline the general concept behind multidimensional laser spectroscopy, for instance by highlighting the often-employed analogy between multidimensional laser spectroscopy and NMR methods. Our initial introduction is followed by an overview of the most important and widely used multidimensional spectroscopies' classification. Special emphasis is placed on how the contributing spectral region defines a natural way of grouping the techniques in terms of their information content. On this basis, we introduce the most important graphical ways in which multidimensional data is generally visualized. This is done by comparing specifically temporal and spectra axes that make up each single multidimensional data plot. Several central experimental methods that are common to the various techniques reviewed in this collection are addressed in the perspective of recent developments and their impact on the field. These methods include, for example, heterodyne/homodyne detection, fast scanning, spatial light modulation, and sparse sampling methods. Importantly, we address the central and fundamental questions where multidimensional ultrafast spectroscopy can be used to help understanding chemical dynamics and intermolecular interactions. Finally, we briefly pinpoint what we believe are the main open questions and what will be the future directions for technical developments and promotion of scientific understanding that multidimensional spectroscopy can provide for chemistry, physics, and life sciences.

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Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP

Abstract: Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain α-helices as well as β-sheets.

Cited by 40 publications

References 81 publications

Amyloid Self‐Assembly of hIAPP8‐20 via the Accumulation of Helical Oligomers, α‐Helix to β‐Sheet Transition, and Formation of β‐Barrel Intermediates

Amyloid Self‐Assembly of hIAPP8‐20 via the Accumulation of Helical Oligomers, α‐Helix to β‐Sheet Transition, and Formation of β‐Barrel Intermediates

Identification of a hinge residue controlling islet amyloid polypeptide self-assembly and cytotoxicity

Introduction to State-of-the-Art Multidimensional Time-Resolved Spectroscopy Methods

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