IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1000241.html
   My bibliography  Save this article

Disordered Flanks Prevent Peptide Aggregation

Author

Listed:
  • Sanne Abeln
  • Daan Frenkel

Abstract

Natively unstructured or disordered regions appear to be abundant in eukaryotic proteins. Many such regions have been found alongside small linear binding motifs. We report a Monte Carlo study that aims to elucidate the role of disordered regions adjacent to such binding motifs. The coarse-grained simulations show that small hydrophobic peptides without disordered flanks tend to aggregate under conditions where peptides embedded in unstructured peptide sequences are stable as monomers or as part of small micelle-like clusters. Surprisingly, the binding free energy of the motif is barely decreased by the presence of disordered flanking regions, although it is sensitive to the loss of entropy of the motif itself upon binding. This latter effect allows for reversible binding of the signalling motif to the substrate. The work provides insights into a mechanism that prevents the aggregation of signalling peptides, distinct from the general mechanism of protein folding, and provides a testable hypothesis to explain the abundance of disordered regions in proteins.Author Summary: In their natural cellular environment proteins are dissolved in a concentrated aqueous solution of biomolecules. Even under such crowded conditions, proteins must not clump together or aggregate; otherwise their biological functions may be compromised, and the cell could die. Diseases such as Parkinson and Alzheimer are thought to be caused by aggregation of specific proteins. Evolutionary pressure generally ensures that proteins do not aggregate in their natural biochemical environment. A well-known mechanism to prevent aggregation is the folding of proteins, where the hydrophobic (attractive) part of the protein is buried inside the protein. Here we report a different mechanism that can prevent the aggregation of proteins. Recently, it was discovered that many proteins contain regions that are disordered (not folded) in their natural environment. We show with coarse-grained simulations that aggregation of small hydrophobic binding motifs can be prevented by embedding the motifs in disordered regions: the disordered regions of different proteins obstruct or sterically hinder the formation of aggregates. Moreover, our simulations show that the disordered regions have no adverse effect on the biological function of the binding motifs, because they do not obstruct the binding and folding of the binding motif on its specific substrate.

Suggested Citation

  • Sanne Abeln & Daan Frenkel, 2008. "Disordered Flanks Prevent Peptide Aggregation," PLOS Computational Biology, Public Library of Science, vol. 4(12), pages 1-7, December.
  • Handle: RePEc:plo:pcbi00:1000241
    DOI: 10.1371/journal.pcbi.1000241
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1000241
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000241&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1000241?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. 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.
    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. Ruchi Lohia & Reza Salari & Grace Brannigan, 2019. "Sequence specificity despite intrinsic disorder: How a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein," PLOS Computational Biology, Public Library of Science, vol. 15(10), pages 1-29, October.

    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. Andrew C Gill, 2014. "β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-17, January.
    2. 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.
    3. 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.
    4. Da-Wei Li & Sandipan Mohanty & Anders Irbäck & Shuanghong Huo, 2008. "Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment," PLOS Computational Biology, Public Library of Science, vol. 4(12), pages 1-12, 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:pcbi00:1000241. 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: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    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.