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

• Published in: The Journal of biological chemistry 2001-12, Vol.276 (50), p.46714
• Main Authors: Fabrizio Chiti, Ersilia De Lorenzi, Silvia Grossi, Palma Mangione, Sofia Giorgetti, Gabriele Caccialanza, Christopher M. Dobson, Giampaolo Merlini, Giampietro Ramponi, Vittorio Bellotti
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M107040200

The folding of β 2 -microglobulin (β 2 -m), the protein forming amyloid deposits in dialysis-related amyloidosis, involves formation of a partially folded conformation named I 2 , which slowly converts into the native fold, N. Here we show that the partially folded species I 2 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 I 2 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 I 2 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 β 2 -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 β 2 -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 β 2 -m but also to design new pharmaceutical approaches that consider such species as a putative molecular target.