Native-unlike long-lived intermediates along the folding pathway of the amyloidogenic protein β2-microglobulin revealed by real-time two-dimensional NMR

Alessandra Corazza, Enrico Rennella, Paul Schanda, Maria Chiara Mimmi, Thomas Cutuil, Sara Raimondi, Sofia Giorgetti, Federico Fogolari, Paolo Viglino, Lucio Frydman, Maayan Gal, Vittorio Bellotti, Bernhard Brutscher, Gennaro Esposito

Research output: Contribution to journalArticlepeer-review


β2-microglobulin (β2m), the light chain of class I major histocompatibility complex, is responsible for the dialysis-related amyloidosis and, in patients undergoing long term dialysis, the full-length and chemically unmodified β2m converts into amyloid fibrils. The protein, belonging to the immunoglobulin superfamily, in common to other members of this family, experiences during its folding a long-lived intermediate associated to the trans-to-cis isomerization of Pro-32 that has been addressed as the precursor of the amyloid fibril formation. In this respect, previous studies on the W60G β2m mutant, showing that the lack of Trp-60 prevents fibril formation in mild aggregating condition, prompted us to reinvestigate the refolding kinetics of wild type and W60G β2m at atomic resolution by real-time NMR. The analysis, conducted at ambient temperature by the band selective flip angle short transient real-time two-dimensional NMR techniques and probing the β2m states every 15 s, revealed a more complex folding energy landscape than previously reported for wild type β2m, involving more than a single intermediate species, and shedding new light into the fibrillogenic pathway. Moreover, a significant difference in the kinetic scheme previously characterized by optical spectroscopic methods was discovered for the W60G β2m mutant.

Original languageEnglish (US)
Pages (from-to)5827-5835
Number of pages9
JournalJournal of Biological Chemistry
Issue number8
StatePublished - Feb 19 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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