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, G. 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
Pages (from-to)1051-1064
Number of pages14
JournalJournal of Molecular Biology
Volume335
Issue number4
DOIs
Publication statusPublished - Jan 23 2004

Keywords

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

ASJC Scopus subject areas

  • Virology

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    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, 335(4), 1051-1064. https://doi.org/10.1016/j.jmb.2003.11.040