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Structural properties of an amyloid precursor of β2-microglobulin

Nature Structural Biology volume 9, pages 326–331 (2002)Cite this article

Abstract

The population of one or more partially folded states has been proposed as a critical initial step in amyloid formation for several proteins. Here we use equilibrium denaturation measured by 1H-15N NMR to determine the conformational properties of an amyloidogenic intermediate of human β2-microglobulin (β2m) formed at low pH. The data show that this amyloid precursor is a noncooperatively stabilized ensemble that retains stable structure in five of the seven β-strands that comprise the native fold. The amyloid precursors of β2m and transthyretin have similar properties despite having structurally unrelated native folds. The data offer a rationale as to why these proteins are both amyloidogenic at low pH and suggest that amyloidosis of these and other proteins may involve ordered assembly from a precursor with similar conformational features.

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Figure 1: 1H-15N HSQC spectra of β2m.
Figure 2: 1H-15N HSQC spectra of β2m at pH 3.6, 25 °C in different concentrations of urea: 0.5 M, 1.5 M, 3 M and 9 M.
Figure 3: Urea denaturation of partially folded β2m.
Figure 4: The conformational properties of partially folded β2m.
Figure 5: Schematic representation of the conformational properties of partially folded β2m at increasing urea concentrations: a, 0 M; b; 1.5 M; and c, 3 M.

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Acknowledgements

We thank A. Baron for performing the ultracentrifugation experiments, A. Ashcroft for mass spectrometry and B. Jakobsen for providing the expression construct for β2m. We are very grateful to M. Sunde, C. Redfield, C. Dobson, J. Kelly, D. Westhead, F. Chiti, A. Berry and members of the S.E.R. group for helpful discussions. We acknowledge with thanks the financial support from The University of Leeds, The Wellcome Trust, British Biotech Pharmaceuticals Ltd. and the BBSRC. V.J.M. is supported by the Wellcome Trust. S.E.R. is a BBSRC Professorial Fellow. The paper is a contribution from the Astbury Centre for Structural Molecular Biology, which is part of the North of England Structural Biology Centre and is supported by the BBSRC.

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  1. School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK

    Victoria J. McParland, Arnout P. Kalverda, Steve W. Homans & Sheena E. Radford

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  1. Victoria J. McParland
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Correspondence to Sheena E. Radford.

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McParland, V., Kalverda, A., Homans, S. et al. Structural properties of an amyloid precursor of β2-microglobulin. Nat Struct Mol Biol 9, 326–331 (2002). https://doi.org/10.1038/nsb791

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