An unusual hydrophobic core confers extreme flexibility to HEAT repeat proteins

C. Kappel, Ulrich Zachariae, N. Dölker, H. Grubmüller

    Research output: Contribution to journalArticle

    40 Citations (Scopus)

    Abstract

    Alpha-solenoid proteins are suggested to constitute highly flexible macromolecules, whose structural variability and large surface area is instrumental in many important protein-protein binding processes. By equilibrium and nonequilibrium molecular dynamics simulations, we show that importin-ß, an archetypical a-solenoid, displays unprecedentedly large and fully reversible elasticity. Our stretching molecular dynamics simulations reveal full elasticity over up to twofold end-to-end extensions compared to its bound state. Despite the absence of any long-range intramolecular contacts, the protein can return to its equilibrium structure to within 3 Å backbone RMSD after the release of mechanical stress. We find that this extreme degree of flexibility is based on an unusually flexible hydrophobic core that differs substantially from that of structurally similar but more rigid globular proteins. In that respect, the core of importin-ß resembles molten globules. The elastic behavior is dominated by nonpolar interactions between HEAT repeats, combined with conformational entropic effects. Our results suggest that a-solenoid structures such as importin-ß may bridge the molecular gap between completely structured and intrinsically disordered proteins.
    Original languageEnglish
    Pages (from-to)1596-1603
    Number of pages8
    JournalBiophysical Journal
    Volume99
    Issue number5
    DOIs
    Publication statusPublished - 8 Sep 2010

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    Karyopherins
    Elasticity
    Molecular Dynamics Simulation
    Proteins
    Intrinsically Disordered Proteins
    Mechanical Stress
    Protein Binding

    Cite this

    Kappel, C. ; Zachariae, Ulrich ; Dölker, N. ; Grubmüller, H. / An unusual hydrophobic core confers extreme flexibility to HEAT repeat proteins. In: Biophysical Journal. 2010 ; Vol. 99, No. 5. pp. 1596-1603.
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    abstract = "Alpha-solenoid proteins are suggested to constitute highly flexible macromolecules, whose structural variability and large surface area is instrumental in many important protein-protein binding processes. By equilibrium and nonequilibrium molecular dynamics simulations, we show that importin-{\ss}, an archetypical a-solenoid, displays unprecedentedly large and fully reversible elasticity. Our stretching molecular dynamics simulations reveal full elasticity over up to twofold end-to-end extensions compared to its bound state. Despite the absence of any long-range intramolecular contacts, the protein can return to its equilibrium structure to within 3 {\AA} backbone RMSD after the release of mechanical stress. We find that this extreme degree of flexibility is based on an unusually flexible hydrophobic core that differs substantially from that of structurally similar but more rigid globular proteins. In that respect, the core of importin-{\ss} resembles molten globules. The elastic behavior is dominated by nonpolar interactions between HEAT repeats, combined with conformational entropic effects. Our results suggest that a-solenoid structures such as importin-{\ss} may bridge the molecular gap between completely structured and intrinsically disordered proteins.",
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    An unusual hydrophobic core confers extreme flexibility to HEAT repeat proteins. / Kappel, C.; Zachariae, Ulrich; Dölker, N.; Grubmüller, H.

    In: Biophysical Journal, Vol. 99, No. 5, 08.09.2010, p. 1596-1603.

    Research output: Contribution to journalArticle

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