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Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity

Author

Listed:
  • Tanguy Le Marchand

    (Université de Lyon)

  • Matteo de Rosa

    (Università degli Studi di Milano)

  • Nicola Salvi

    (Institut de Biologie Structurale, CNRS, CEA, UGA)

  • Benedetta Maria Sala

    (Università degli Studi di Milano)

  • Loren B. Andreas

    (Université de Lyon)

  • Emeline Barbet-Massin

    (Université de Lyon)

  • Pietro Sormanni

    (University of Cambridge)

  • Alberto Barbiroli

    (Università degli Studi di Milano)

  • Riccardo Porcari

    (University College London)

  • Cristiano Sousa Mota

    (ESRF - The European Synchrotron)

  • Daniele de Sanctis

    (ESRF - The European Synchrotron)

  • Martino Bolognesi

    (Università degli Studi di Milano
    Università degli Studi di Milano)

  • Lyndon Emsley

    (Université de Lyon)

  • Vittorio Bellotti

    (University College London)

  • Martin Blackledge

    (Institut de Biologie Structurale, CNRS, CEA, UGA)

  • Carlo Camilloni

    (Università degli Studi di Milano)

  • Guido Pintacuda

    (Université de Lyon)

  • Stefano Ricagno

    (Università degli Studi di Milano)

Abstract

Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (β2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of β2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline β2m. The destabilization of the outer strands of D76N β2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.

Suggested Citation

  • Tanguy Le Marchand & Matteo de Rosa & Nicola Salvi & Benedetta Maria Sala & Loren B. Andreas & Emeline Barbet-Massin & Pietro Sormanni & Alberto Barbiroli & Riccardo Porcari & Cristiano Sousa Mota & D, 2018. "Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04078-y
    DOI: 10.1038/s41467-018-04078-y
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    Cited by:

    1. Martin Wilkinson & Rodrigo U. Gallardo & Roberto Maya Martinez & Nicolas Guthertz & Masatomo So & Liam D. Aubrey & Sheena E. Radford & Neil A. Ranson, 2023. "Disease-relevant β2-microglobulin variants share a common amyloid fold," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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