期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 18, 页码 9678-9689出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.720573
关键词
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资金
- United Kingdom Medical Research Council [MR/K000187/1]
- Italian Ministry of University and Research Project FIRB [RBFR109EOS]
- Telethon Grant [GG14127]
- Cariplo Foundation [2013-0964, 2014-0700]
- Istituto Nazionale di Biostrutture e Biosistemi
- Medical Research Council [MR/K000187/1] Funding Source: researchfish
- MRC [MR/K000187/1] Funding Source: UKRI
The amyloidogenic variant of beta(2)-microglobulin, D76N, can readily convert into genuine fibrils under physiological conditions and primes in vitro the fibrillogenesis of the wild-type beta(2)-microglobulin. By Fourier transformed infrared spectroscopy, we have demonstrated that the amyloid transformation of wild-type beta(2)-microglobulin can be induced by the variant only after its complete fibrillar conversion. Our current findings are consistent with preliminary data in which we have shown a seeding effect of fibrils formed from D76N or the natural truncated form of beta(2)-microglobulin lacking the first six N-terminal residues. Interestingly, the hybrid wild-type/variant fibrillar material acquired a thermodynamic stability similar to that of homogenous D76N beta(2)-microglobulin fibrils and significantly higher than the wild-type homogeneous fibrils prepared at neutral pH in the presence of 20% trifluoroethanol. These results suggest that the surfaceofD76N beta(2)-microglobulinfibrilscanfavorthetransitionof the wild-type protein into an amyloid conformation leading to a rapid integration into fibrils. The chaperone crystallin, which is a mild modulator of the lag phase of the variant fibrillogenesis, potently inhibits fibril elongation of the wild-type even once it is absorbed on D76N beta(2)-microglobulin fibrils.
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