β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation

C. Rosano, S. Zuccotti, P. Mangione, S. Giorgetti, V. Bellotti, F. Pettirossi, A. Corazza, P. Viglino, Gennaro Esposito, M. Bolognesi

    Research output: Contribution to journalArticle

    Abstract

    β2-Microglobulin (β2m) is the non-covalently bound light chain of the human class I major histocompatibility complex (MHC-I). The natural turnover of MHC-I gives rise to the release of β2m into plasmatic fluids and to its catabolism in the kidney. β2m dissociation from the heavy chain of the complex is a severe complication in patients receiving prolonged hemodialysis. As a consequence of renal failure, the increasing β2m concentrations can lead to deposition of the protein as amyloid fibrils. Here we characterize the His31→Tyr human β2m mutant, a non-natural form of β2m that is more stable than the wild-type protein, displaying a ten-fold acceleration of the slow phase of folding. We report the 2.9Å resolution crystal structure and the NMR characterization of the mutant β2m, focussing on selected structural features and on the molecular packing observed in the crystals. Juxtaposition of the four mutant β2m molecules contained in the crystal asymmetric unit, and specific hydrogen bonds, stabilize a compact protein assembly. Conformational heterogeneity of the four independent molecules, some of their mutual interactions and partial unpairing of the N-terminal β-strand in one protomer are in keeping with the amyloidogenic properties displayed by the mutant β2m.

    Original languageEnglish (US)
    Pages (from-to)1051-1064
    Number of pages14
    JournalJournal of Molecular Biology
    Volume335
    Issue number4
    DOIs
    StatePublished - Jan 23 2004

    Fingerprint

    Major Histocompatibility Complex
    Proteins
    Protein Subunits
    Amyloid
    Renal Insufficiency
    Renal Dialysis
    Hydrogen
    Kidney
    Light

    Keywords

    • Amyloid aggregate
    • NMR structure
    • Protein structure
    • X-ray crystallography
    • β2-microglobulin

    ASJC Scopus subject areas

    • Molecular Biology

    Cite this

    Rosano, C., Zuccotti, S., Mangione, P., Giorgetti, S., Bellotti, V., Pettirossi, F., ... Bolognesi, M. (2004). β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation. Journal of Molecular Biology, 335(4), 1051-1064. https://doi.org/10.1016/j.jmb.2003.11.040

    β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation. / Rosano, C.; Zuccotti, S.; Mangione, P.; Giorgetti, S.; Bellotti, V.; Pettirossi, F.; Corazza, A.; Viglino, P.; Esposito, Gennaro; Bolognesi, M.

    In: Journal of Molecular Biology, Vol. 335, No. 4, 23.01.2004, p. 1051-1064.

    Research output: Contribution to journalArticle

    Rosano, C, Zuccotti, S, Mangione, P, Giorgetti, S, Bellotti, V, Pettirossi, F, Corazza, A, Viglino, P, Esposito, G & Bolognesi, M 2004, 'β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation', Journal of Molecular Biology, vol. 335, no. 4, pp. 1051-1064. https://doi.org/10.1016/j.jmb.2003.11.040
    Rosano, C. ; Zuccotti, S. ; Mangione, P. ; Giorgetti, S. ; Bellotti, V. ; Pettirossi, F. ; Corazza, A. ; Viglino, P. ; Esposito, Gennaro ; Bolognesi, M. / β2-Microglobulin H31Y Variant 3D Structure Highlights the Protein Natural Propensity Towards Intermolecular Aggregation. In: Journal of Molecular Biology. 2004 ; Vol. 335, No. 4. pp. 1051-1064.
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    AU - Giorgetti, S.

    AU - Bellotti, V.

    AU - Pettirossi, F.

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