Elucidating the fine structure of amyloid fibrils as well as understanding their processes of nucleation and growth remains a difficult yet essential challenge, directly linked to our current poor insight into protein misfolding and aggregation diseases. Here we consider beta-2-microglobulin (beta 2m), the MHC-1 light chain component responsible for dialysis-related amyloidosis, which can give rise to amyloid fibrils in vitro under various experimental conditions, including low and neutral pH. We have used solid-state NMR to probe the structural features of fibrils formed by full-length beta 2m (99 residues) at pH 2.5 and pH 7.4. A close comparison of 2D C-13-C-13 and N-15-C-13 correlation experiments performed on beta 2m, in both the crystalline and fibrillar states, suggests that, in spite of structural changes affecting the protein loops linking the protein B-strands, the protein chain retains a substantial share of its native secondary structure in the fibril assembly. Moreover, variations in the chemical shifts of the key Pro32 residue suggest the involvement of a cis-trans isomerization in the process of beta 2m fibril formation. Lastly, the analogy of the spectra recorded on beta 2m fibrils grown at different pH values hints at a conserved architecture of the amyloid species thus obtained.
Fibrillar vs Crystalline Full-Length β-2-Microglobulin Studied by High-Resolution Solid-State NMR Spectroscopy / E. Barbet Massin, S. Ricagno, J.R. Lewandowski, S. Giorgetti, V. Bellotti, M. Bolognesi, L. Emsley, G. Pintacuda. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - 132:16(2010), pp. 5556-5557. [10.1021/ja1002839]
Fibrillar vs Crystalline Full-Length β-2-Microglobulin Studied by High-Resolution Solid-State NMR Spectroscopy
S. RicagnoSecondo
;M. Bolognesi;
2010
Abstract
Elucidating the fine structure of amyloid fibrils as well as understanding their processes of nucleation and growth remains a difficult yet essential challenge, directly linked to our current poor insight into protein misfolding and aggregation diseases. Here we consider beta-2-microglobulin (beta 2m), the MHC-1 light chain component responsible for dialysis-related amyloidosis, which can give rise to amyloid fibrils in vitro under various experimental conditions, including low and neutral pH. We have used solid-state NMR to probe the structural features of fibrils formed by full-length beta 2m (99 residues) at pH 2.5 and pH 7.4. A close comparison of 2D C-13-C-13 and N-15-C-13 correlation experiments performed on beta 2m, in both the crystalline and fibrillar states, suggests that, in spite of structural changes affecting the protein loops linking the protein B-strands, the protein chain retains a substantial share of its native secondary structure in the fibril assembly. Moreover, variations in the chemical shifts of the key Pro32 residue suggest the involvement of a cis-trans isomerization in the process of beta 2m fibril formation. Lastly, the analogy of the spectra recorded on beta 2m fibrils grown at different pH values hints at a conserved architecture of the amyloid species thus obtained.Pubblicazioni consigliate
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