Oligomeric states along the folding pathways of β2-microglobulin

Kinetics, thermodynamics, and structure

E. Rennella, T. Cutuil, P. Schanda, I. Ayala, F. Gabel, V. Forge, A. Corazza, Gennaro Esposito, B. Brutscher

    Research output: Contribution to journalArticle

    Abstract

    The transition of proteins from their soluble functional state to amyloid fibrils and aggregates is associated with the onset of several human diseases. Protein aggregation often requires some structural reshaping and the subsequent formation of intermolecular contacts. Therefore, the study of the conformation of excited protein states and their ability to form oligomers is of primary importance for understanding the molecular basis of amyloid fibril formation. Here, we investigated the oligomerization processes that occur along the folding of the amyloidogenic human protein β2-microglobulin. The combination of real-time two-dimensional NMR data with real-time small-angle X-ray scattering measurements allowed us to derive thermodynamic and kinetic information on protein oligomerization of different conformational states populated along the folding pathways. In particular, we could demonstrate that a long-lived folding intermediate (I-state) has a higher propensity to oligomerize compared to the native state. Our data agree well with a simple five-state kinetic model that involves only monomeric and dimeric species. The dimers have an elongated shape with the dimerization interface located at the apical side of β2-microglobulin close to Pro32, the residue that has a trans conformation in the I-state and a cis conformation in the native (N) state. Our experimental data suggest that partial unfolding in the apical half of the protein close to Pro32 leads to an excited state conformation with enhanced propensity for oligomerization. This excited state becomes more populated in the transient I-state due to the destabilization of the native conformation by the trans-Pro32 configuration.

    Original languageEnglish (US)
    Pages (from-to)2722-2736
    Number of pages15
    JournalJournal of Molecular Biology
    Volume425
    Issue number15
    DOIs
    StatePublished - Aug 9 2013

    Fingerprint

    Thermodynamics
    Amyloid
    Proteins
    Amyloidogenic Proteins
    Protein Conformation
    Dimerization
    X-Rays

    Keywords

    • folding amyloid formation
    • NMR
    • oligomers
    • real-time
    • SAXS protein

    ASJC Scopus subject areas

    • Molecular Biology

    Cite this

    Rennella, E., Cutuil, T., Schanda, P., Ayala, I., Gabel, F., Forge, V., ... Brutscher, B. (2013). Oligomeric states along the folding pathways of β2-microglobulin: Kinetics, thermodynamics, and structure. Journal of Molecular Biology, 425(15), 2722-2736. https://doi.org/10.1016/j.jmb.2013.04.028

    Oligomeric states along the folding pathways of β2-microglobulin : Kinetics, thermodynamics, and structure. / Rennella, E.; Cutuil, T.; Schanda, P.; Ayala, I.; Gabel, F.; Forge, V.; Corazza, A.; Esposito, Gennaro; Brutscher, B.

    In: Journal of Molecular Biology, Vol. 425, No. 15, 09.08.2013, p. 2722-2736.

    Research output: Contribution to journalArticle

    Rennella, E, Cutuil, T, Schanda, P, Ayala, I, Gabel, F, Forge, V, Corazza, A, Esposito, G & Brutscher, B 2013, 'Oligomeric states along the folding pathways of β2-microglobulin: Kinetics, thermodynamics, and structure', Journal of Molecular Biology, vol. 425, no. 15, pp. 2722-2736. https://doi.org/10.1016/j.jmb.2013.04.028
    Rennella, E. ; Cutuil, T. ; Schanda, P. ; Ayala, I. ; Gabel, F. ; Forge, V. ; Corazza, A. ; Esposito, Gennaro ; Brutscher, B. / Oligomeric states along the folding pathways of β2-microglobulin : Kinetics, thermodynamics, and structure. In: Journal of Molecular Biology. 2013 ; Vol. 425, No. 15. pp. 2722-2736.
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    AU - Ayala, I.

    AU - Gabel, F.

    AU - Forge, V.

    AU - Corazza, A.

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