A Partially Structured Species of β2-Microglobulin Is Significantly Populated under Physiological Conditions and Involved in Fibrillogenesis

Fabrizio Chiti, Ersilia De Lorenzi, Silvia Grossi, Palma Mangione, Sofia Giorgetti, Gabriele Caccialanza, Christopher M. Dobson, Giampaolo Merlini, Giampietro Ramponi, Vittorio Bellotti

Research output: Contribution to journalArticle

Abstract

The folding of β2-microglobulin (β2-m), the protein forming amyloid deposits in dialysis-related amyloidosis, involves formation of a partially folded conformation named I2, which slowly converts into the native fold, N. Here we show that the partially folded species I2 can be separated from N by capillary electrophoresis. Data obtained with this technique and analysis of kinetic data obtained with intrinsic fluorescence indicate that the I2 conformation is populated to ∼14 ± 8% at equilibrium under conditions of pH and temperature close to physiological. In the presence of fibrils extracted from patients, the I2 conformer has a 5-fold higher propensity to aggregate than N, as indicated by the thioflavine T test and light scattering measurements. A mechanism of aggregation of β2-m in vivo involving the association of the preformed fibrils with the fraction of I 2 existing at equilibrium is proposed from these results. The possibility of isolating and quantifying a partially folded conformer of β2-m involved in the amyloidogenesis process provides new opportunities to monitor hemodialytic procedures aimed at the reduction of such species from the pool of circulating β2-m but also to design new pharmaceutical approaches that consider such species as a putative molecular target.

Original languageEnglish
Pages (from-to)46714-46721
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number50
DOIs
Publication statusPublished - Dec 14 2001

ASJC Scopus subject areas

  • Biochemistry

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    Chiti, F., De Lorenzi, E., Grossi, S., Mangione, P., Giorgetti, S., Caccialanza, G., Dobson, C. M., Merlini, G., Ramponi, G., & Bellotti, V. (2001). A Partially Structured Species of β2-Microglobulin Is Significantly Populated under Physiological Conditions and Involved in Fibrillogenesis. Journal of Biological Chemistry, 276(50), 46714-46721. https://doi.org/10.1074/jbc.M107040200