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Co-fibrillogenesis of Wild-type and D76N β₂-Microglobulin: THE CRUCIAL ROLE OF FIBRILLAR SEEDS

Natalello, A; Mangione, PP; Giorgetti, S; Porcari, R; Marchese, L; Zorzoli, I; Relini, A; ... Raimondi, S; + view all (2016) Co-fibrillogenesis of Wild-type and D76N β₂-Microglobulin: THE CRUCIAL ROLE OF FIBRILLAR SEEDS. Journal of Biological Chemistry , 291 (18) pp. 9678-9689. 10.1074/jbc.M116.720573. Green open access

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Abstract

The amyloidogenic variant of β2-microglobulin, D76N, can readily convert into genuine fibrils under physiological conditions and primes in vitro the fibrillogenesis of the wild-type β2-microglobulin. By Fourier transformed infrared spectroscopy, we have demonstrated that the amyloid transformation of wild-type β2-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 β2-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 β2-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 surface of D76N β2-microglobulin fibrils can favor the transition of 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 β2-microglobulin fibrils.

Type: Article
Title: Co-fibrillogenesis of Wild-type and D76N β₂-Microglobulin: THE CRUCIAL ROLE OF FIBRILLAR SEEDS
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M116.720573
Publisher version: http://dx.doi.org/10.1074/jbc.M116.720573
Language: English
Additional information: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0).
Keywords: amyloid, fibril, Fourier transform IR (FTIR), protein aggregation, protein misfolding, β2-microglobulin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/1490493
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