期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 8, 页码 5827-5835出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.061168
关键词
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资金
- Ministero dell'Istruzione, dell'Universita e della Ricerca [RBNE03PX83, RBRN07BMCT, PRIN 2007_XY59ZJ_002]
- European Union (EU) [LSHM-CT-2005-037525]
- EU-NMR [026145]
- French Agence Nationale pour la Recherche [ANR-08-BLAN-0210]
- Agence Nationale de la Recherche (ANR) [ANR-08-BLAN-0210] Funding Source: Agence Nationale de la Recherche (ANR)
beta 2-microglobulin (beta 2m), 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 beta 2m 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 beta 2m 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 beta 2m 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 beta 2m states every 15 s, revealed a more complex folding energy landscape than previously reported for wild type beta 2m, 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 beta 2m mutant.
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