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Fibrillar vs crystalline full-length β-2-microglobulin studied by high-resolution solid-state NMR spectroscopy

By Emeline Barbet-Massin, Stefano Ricagno, Józef R. Lewandowski, Sofia Giorgetti, Vittorio Bellotti, Martino Bolognesi, Lyndon Emsley and Guido Pintacuda

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 (13)C-(13)C and (15)N-(13)C 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

Topics: QD, QP
Publisher: American Chemical Society
Year: 2010
DOI identifier: 10.1021/ja1002839
OAI identifier: oai:wrap.warwick.ac.uk:40593
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