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Crystal structure of monomeric human β-2- microglobulin reveals clues to its amyloidogenic properties

Trinh, C.H., Smith, D.P., Arnout, P.K., Phillips, S.E.V. and Radford, S.E. (2002) Crystal structure of monomeric human β-2- microglobulin reveals clues to its amyloidogenic properties. Proceedings of the National Academy of Sciences, 99 (15). pp. 9771-9776. ISSN 0027-8424

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Abstract

Dissociation of human β-2-microglobulin (β(2)m) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric β(2)m increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human β(2)m determined at 1.8-Å resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a β bulge that separates two short β strands to form a new six-residue β strand at one edge of this β sandwich protein. These structural changes remove key features proposed to have evolved to protect β sheet proteins from aggregation [Richardson, J.&Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754–2759] and replaces them with an aggregationcompetent surface. In combination with solution studies using (1)H NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein.

Item Type: Article
Copyright, Publisher and Additional Information: © Copyright 2002 National Academy of Sciences, U.S.A.
Institution: The University of Leeds
Academic Units: The University of Leeds > University of Leeds Research Centres and Institutes > Astbury Centre for Structural Molecular Biology (Leeds)
The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute of Molecular and Cellular Biology (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 13 Mar 2006
Last Modified: 07 Jun 2014 00:12
Published Version: http://www.pnas.org/cgi/reprint/99/15/9771
Status: Published
Refereed: Yes
Identification Number: 10.1073/pnas.152337399
URI: http://eprints.whiterose.ac.uk/id/eprint/574

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