Solution structure of β2-microglobulin and insights into fibrillogenesis

Gennaro Esposito, Alessandra Corazza, Paolo Viglino, Giuliana Verdone, Fabio Pettirossi, Federico Fogolari, Ads Makek, Sofia Giorgetti, Palma Mangione, Monica Stoppini, Vittorio Bellotti

Research output: Contribution to journalArticle

Abstract

The solution structure of human β2-microglobulin (β2-m) was determined by 1H NMR spectroscopy and restrained modeling calculations. Compared to the crystal structure of type I major histocompatibility complex (MHC-I), where the protein is associated to the heavy-chain component, several differences are observed, i.e., increased separation between strands A and B, displacements of strand C′ and loop DE, shortening of strands D and E. These modifications can be considered as the prodromes of the amyloid transition. Even minor charge changes in response to pH, as is the case with H31 imidazole protonation, trigger the transition that starts with unpairing of strand A. The same mechanism accounts for the partial unfolding and fiber formation subsequent to Cu2+ binding which is shown to occur primarily at H31. Solvation of the protected regions in MHC-I decreases the tertiary packing by breaking the contiguity of the surface hydrophobic patches via surface charge cluster. Mutants or truncated forms of β2-m can be designed to remove the instability from H31 titration or to enhance the instability through surface charge suppression. By monitoring the conformational evolution of wild-type protein and variants thereof, either in response or absence of external perturbation, valuable insights into intermediate structure and fibrillogenesis mechanisms are gained.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1753
Issue number1
DOIs
StatePublished - Nov 10 2005

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Keywords

  • Amyloidogenic protein NMR
  • Protein NMR
  • β- microglobulin NMR structure
  • β- microglobulin mutant
  • β-microglobulin conformation
  • β-microglobulin solution structure

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Esposito, G., Corazza, A., Viglino, P., Verdone, G., Pettirossi, F., Fogolari, F., Makek, A., Giorgetti, S., Mangione, P., Stoppini, M., & Bellotti, V. (2005). Solution structure of β2-microglobulin and insights into fibrillogenesis. Biochimica et Biophysica Acta - Proteins and Proteomics, 1753(1), 76-84. https://doi.org/10.1016/j.bbapap.2005.07.003