Folding and Fibrillogenesis: Clues from β 2 -Microglobulin Enrico Rennella 1,2 , Alessandra Corazza 1,2 , Sofia Giorgetti 2,3,4 , Federico Fogolari 1,2 , Paolo Viglino 1,2 , Riccardo Porcari 3 , Laura Verga 5 , Monica Stoppini 2,3 , Vittorio Bellotti 2,3,4 and Gennaro Esposito 1,2 ⁎ 1 Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, I-33100 Udine,Italy 2 Istituto Nazionale Biostrutture e Biosistemi, I-00136 Rome, Italy 3 Dipartimento di Biochimica, Università di Pavia, I-27100 Pavia,Italy 4 Laboratori di Biotecnologie, Centro Amiloidosi, IRCCS Policlinico S. Matteo, I-27100 Pavia,Italy 5 Dipartimento di Patologia Umana ed Ereditaria, Sezione Anatomia Patologica, IRCCS Policlinico S. Matteo, I-27100 Pavia,Italy Received 3 February 2010; received in revised form 7 June 2010; accepted 8 June 2010 Available online 15 June 2010 Renalfailure impairs the clearance of β 2 -microglobulin from the serum, with the resultthat this protein accumulates in joints under the form of amyloid fibrils.While the molecular mechanism leading to deposition of amyloid in vivo is not totally understood, some organic compounds, such as trifluoroethanol (TFE), are commonly used to promote the elongation of amyloid fibrils in vitro. This article gives some insights into the structural properties and the conformational states of β 2 -microglobulin in the presence of TFE, using both the wild-type protein and the mutant Trp60Gly. The structure ofthe native state ofthe protein is ratherinsensitive to the presenceof the alcohol, but the stability of this state is lowered in comparison to some other conformational states. In particular, a native-like folding intermediate is observed in the presence of moderate concentrations of TFE. Instead, at higher concentrations of the alcohol, the population of a disordered native-unlike state is dominant and correlates with the ability to elongate fibrils. © 2010 Elsevier Ltd. All rights reserved. Edited by P.Wright Keywords: amyloid fibrils;β 2 -microglobulin; folding intermediate; protein thermodynamics; dialysis-related amyloidosis doi:10.1016/j.jmb.2010.06.016 J. Mol. Biol. (2010) 401, 286–297 Available online at www.sciencedirect.com