Structure of an early native-like intermediate of β2-microglobulin amyloidogenesis

Authors

  • Saskia Vanderhaegen,

    1. Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
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  • Marcus Fislage,

    1. Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
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  • Katarzyna Domanska,

    1. Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
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  • Wim Versées,

    1. Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
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  • Els Pardon,

    1. Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
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  • Vittorio Bellotti,

    1. Department of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia, Italy
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  • Jan Steyaert

    Corresponding author
    1. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, Brussel, Belgium
    • Structural Biology Research Centre, VIB, Pleinlaan 2, Brussel, Belgium
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Correspondence to: Structural Biology Research Centre, VIB, Pleinlaan 2, 1050 Brussel, Belgium. E-mail: Jan.Steyaert@vub.ac.be

Abstract

To investigate early intermediates of β2-microglobulin (β2m) amyloidogenesis, we solved the structure of β2m containing the amyloidogenic Pro32Gly mutation by X-ray crystallography. One nanobody (Nb24) that efficiently blocks fibril elongation was used as a chaperone to co-crystallize the Pro32Gly β2m monomer under physiological conditions. The complex of P32G β2m with Nb24 reveals a trans peptide bond at position 32 of this amyloidogenic variant, whereas Pro32 adopts the cis conformation in the wild-type monomer, indicating that the cis to trans isomerization at Pro32 plays a critical role in the early onset of β2m amyloid formation.

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