IDEAS home Printed from https://ideas.repec.org/a/plo/pbio00/0050134.html
   My bibliography  Save this article

A Helical Structural Nucleus Is the Primary Elongating Unit of Insulin Amyloid Fibrils

Author

Listed:
  • Bente Vestergaard
  • Minna Groenning
  • Manfred Roessle
  • Jette S Kastrup
  • Marco van de Weert
  • James M Flink
  • Sven Frokjaer
  • Michael Gajhede
  • Dmitri I Svergun

Abstract

Although amyloid fibrillation is generally believed to be a nucleation-dependent process, the nuclei are largely structurally uncharacterized. This is in part due to the inherent experimental challenge associated with structural descriptions of individual components in a dynamic multi-component equilibrium. There are indications that oligomeric aggregated precursors of fibrillation, and not mature fibrils, are the main cause of cytotoxicity in amyloid disease. This further emphasizes the importance of characterizing early fibrillation events. Here we present a kinetic x-ray solution scattering study of insulin fibrillation, revealing three major components: insulin monomers, mature fibrils, and an oligomeric species. Low-resolution three-dimensional structures are determined for the fibril repeating unit and for the oligomer, the latter being a helical unit composed of five to six insulin monomers. This helical oligomer is likely to be a structural nucleus, which accumulates above the supercritical concentration used in our experiments. The growth rate of the fibrils is proportional to the amount of the helical oligomer present in solution, suggesting that these oligomers elongate the fibrils. Hence, the structural nucleus and elongating unit in insulin amyloid fibrillation may be the same structural component above supercritical concentrations. A novel elongation pathway of insulin amyloid fibrils is proposed, based on the shape and size of the fibrillation precursor. The distinct helical oligomer described in this study defines a conceptually new basis of structure-based drug design against amyloid diseases. : Diseases associated with the presence of amyloid structures, such as Alzheimer and Parkinson disease, are characterized by the presence of protein aggregates in the form of highly ordered fibrils. This amyloid fibril formation is also commonly observed for a number of protein drugs, such as insulin. Detailed information on how and why these fibrils are formed will be very useful to design compounds and drugs that may reverse or even prevent fibril formation, but existing knowledge in this field is still limited. We have studied, in real time, the fibril formation of insulin using a technique based on scattering of x-rays (small-angle x-ray scattering [SAXS]). Using SAXS, we obtained hitherto unprecedented three-dimensional structural information on these fibrils in solution. Most importantly, we were able to describe the three-dimensional structure of a crucial intermediate, which is probably a structural starting point (nucleus) in the fibril formation process. These results suggest that under our experimental conditions this crucial intermediate serves both as the fibrillation nucleus, as well as the elongating species. We propose that the latter intermediate is an interesting target for small molecules in order to prevent or reduce amyloid fibril formation. Insulin fibrillation in solution is studied using small-molecule x-ray scattering. This study provides insights into the early stages of amyloid fibrillation, revealing the amyloid fibril repeat unit and evidence of a helical oligomer.

Suggested Citation

  • Bente Vestergaard & Minna Groenning & Manfred Roessle & Jette S Kastrup & Marco van de Weert & James M Flink & Sven Frokjaer & Michael Gajhede & Dmitri I Svergun, 2007. "A Helical Structural Nucleus Is the Primary Elongating Unit of Insulin Amyloid Fibrils," PLOS Biology, Public Library of Science, vol. 5(5), pages 1-9, May.
  • Handle: RePEc:plo:pbio00:0050134
    DOI: 10.1371/journal.pbio.0050134
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050134
    Download Restriction: no

    File URL: https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0050134&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pbio.0050134?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Christopher M. Dobson, 2003. "Protein folding and misfolding," Nature, Nature, vol. 426(6968), pages 884-890, December.
    2. Monica Bucciantini & Elisa Giannoni & Fabrizio Chiti & Fabiana Baroni & Lucia Formigli & Jesús Zurdo & Niccolò Taddei & Giampietro Ramponi & Christopher M. Dobson & Massimo Stefani, 2002. "Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases," Nature, Nature, vol. 416(6880), pages 507-511, April.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Victor Banerjee & Rajiv K Kar & Aritreyee Datta & Krupakar Parthasarathi & Subhrangsu Chatterjee & Kali P Das & Anirban Bhunia, 2013. "Use of a Small Peptide Fragment as an Inhibitor of Insulin Fibrillation Process: A Study by High and Low Resolution Spectroscopy," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-15, August.
    2. Julian Stirling & Ioannis Lekkas & Adam Sweetman & Predrag Djuranovic & Quanmin Guo & Brian Pauw & Josef Granwehr & Raphaël Lévy & Philip Moriarty, 2014. "Critical Assessment of the Evidence for Striped Nanoparticles," PLOS ONE, Public Library of Science, vol. 9(11), pages 1-18, November.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Mookyung Cheon & Iksoo Chang & Sandipan Mohanty & Leila M Luheshi & Christopher M Dobson & Michele Vendruscolo & Giorgio Favrin, 2007. "Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils," PLOS Computational Biology, Public Library of Science, vol. 3(9), pages 1-12, September.
    2. Qi Wang & Joshua L Johnson & Nathalie YR Agar & Jeffrey N Agar, 2008. "Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival," PLOS Biology, Public Library of Science, vol. 6(7), pages 1-19, July.
    3. Noah S Bieler & Tuomas P J Knowles & Daan Frenkel & Robert Vácha, 2012. "Connecting Macroscopic Observables and Microscopic Assembly Events in Amyloid Formation Using Coarse Grained Simulations," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-10, October.
    4. Arthur Fischbach & Angela Johns & Kara L. Schneider & Xinxin Hao & Peter Tessarz & Thomas Nyström, 2023. "Artificial Hsp104-mediated systems for re-localizing protein aggregates," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Victor Banerjee & Rajiv K Kar & Aritreyee Datta & Krupakar Parthasarathi & Subhrangsu Chatterjee & Kali P Das & Anirban Bhunia, 2013. "Use of a Small Peptide Fragment as an Inhibitor of Insulin Fibrillation Process: A Study by High and Low Resolution Spectroscopy," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-15, August.
    6. Corina N. D’Alessandro-Gabazza & Taro Yasuma & Tetsu Kobayashi & Masaaki Toda & Ahmed M. Abdel-Hamid & Hajime Fujimoto & Osamu Hataji & Hiroki Nakahara & Atsuro Takeshita & Kota Nishihama & Tomohito O, 2022. "Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    7. Kübra Kaygisiz & Lena Rauch-Wirth & Arghya Dutta & Xiaoqing Yu & Yuki Nagata & Tristan Bereau & Jan Münch & Christopher V. Synatschke & Tanja Weil, 2023. "Data-mining unveils structure–property–activity correlation of viral infectivity enhancing self-assembling peptides," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Jian Tian & Jaie C Woodard & Anna Whitney & Eugene I Shakhnovich, 2015. "Thermal Stabilization of Dihydrofolate Reductase Using Monte Carlo Unfolding Simulations and Its Functional Consequences," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-27, April.
    9. Matthias M. Schneider & Saurabh Gautam & Therese W. Herling & Ewa Andrzejewska & Georg Krainer & Alyssa M. Miller & Victoria A. Trinkaus & Quentin A. E. Peter & Francesco Simone Ruggeri & Michele Vend, 2021. "The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    10. Eri Chatani & Yutaro Tsuchisaka & Yuki Masuda & Roumiana Tsenkova, 2014. "Water Molecular System Dynamics Associated with Amyloidogenic Nucleation as Revealed by Real Time Near Infrared Spectroscopy and Aquaphotomics," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-10, July.
    11. Aaron M Streets & Yannick Sourigues & Ron R Kopito & Ronald Melki & Stephen R Quake, 2013. "Simultaneous Measurement of Amyloid Fibril Formation by Dynamic Light Scattering and Fluorescence Reveals Complex Aggregation Kinetics," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-10, January.
    12. Etienne Maisonneuve & Adrien Ducret & Pierre Khoueiry & Sabrina Lignon & Sonia Longhi & Emmanuel Talla & Sam Dukan, 2009. "Rules Governing Selective Protein Carbonylation," PLOS ONE, Public Library of Science, vol. 4(10), pages 1-12, October.
    13. Stefan Auer & Filip Meersman & Christopher M Dobson & Michele Vendruscolo, 2008. "A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates," PLOS Computational Biology, Public Library of Science, vol. 4(11), pages 1-7, November.
    14. Espinoza Ortiz, J.S. & Dias, Cristiano L., 2018. "Cooperative fibril model: Native, amyloid-like fibril and unfolded states of proteins," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 511(C), pages 154-165.
    15. Morten S Dueholm & Daniel Otzen & Per Halkjær Nielsen, 2013. "Evolutionary Insight into the Functional Amyloids of the Pseudomonads," PLOS ONE, Public Library of Science, vol. 8(10), pages 1-1, October.
    16. Sheng Chen & Anuradhika Puri & Braxton Bell & Joseph Fritsche & Hector H. Palacios & Maurie Balch & Macy L. Sprunger & Matthew K. Howard & Jeremy J. Ryan & Jessica N. Haines & Gary J. Patti & Albert A, 2024. "HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Pengfei Tian & Kresten Lindorff-Larsen & Wouter Boomsma & Mogens Høgh Jensen & Daniel Erik Otzen, 2016. "A Monte Carlo Study of the Early Steps of Functional Amyloid Formation," PLOS ONE, Public Library of Science, vol. 11(1), pages 1-18, January.
    18. Allen W Bryan Jr. & Matthew Menke & Lenore J Cowen & Susan L Lindquist & Bonnie Berger, 2009. "BETASCAN: Probable β-amyloids Identified by Pairwise Probabilistic Analysis," PLOS Computational Biology, Public Library of Science, vol. 5(3), pages 1-11, March.
    19. Sanne Abeln & Michele Vendruscolo & Christopher M Dobson & Daan Frenkel, 2014. "A Simple Lattice Model That Captures Protein Folding, Aggregation and Amyloid Formation," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-8, January.
    20. Morten S Dueholm & Mads Albertsen & Daniel Otzen & Per Halkjær Nielsen, 2012. "Curli Functional Amyloid Systems Are Phylogenetically Widespread and Display Large Diversity in Operon and Protein Structure," PLOS ONE, Public Library of Science, vol. 7(12), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pbio00:0050134. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosbiology (email available below). General contact details of provider: https://journals.plos.org/plosbiology/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.