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J. Biol. Chem., Vol. 283, Issue 25, 17279-17286, June 20, 2008

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A Common β-Sheet Architecture Underlies in Vitro and in Vivo β₂-Microglobulin Amyloid Fibrils^*

Thomas R. Jahn¹, Glenys A. Tennent, and Sheena E. Radford²

From the Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom and the Centre for Amyloidosis and Acute Phase Proteins, University College London, London NW3 2PF, United Kingdom

Misfolding and aggregation of normally soluble proteins into amyloid fibrils and their deposition and accumulation underlies a variety of clinically significant diseases. Fibrillar aggregates with amyloid-like properties can also be generated in vitro from pure proteins and peptides, including those not known to be associated with amyloidosis. Whereas biophysical studies of amyloid-like fibrils formed in vitro have provided important insights into the molecular mechanisms of amyloid generation and the structural properties of the fibrils formed, amyloidogenic proteins are typically exposed to mild or more extreme denaturing conditions to induce rapid fibril formation in vitro. Whether the structure of the resulting assemblies is representative of their natural in vivo counterparts, thus, remains a fundamental unresolved issue. Here we show using Fourier transform infrared spectroscopy that amyloid-like fibrils formed in vitro from natively folded or unfolded β₂-microglobulin (the protein associated with dialysis-related amyloidosis) adopt an identical β-sheet architecture. The same β-strand signature is observed whether fibril formation in vitro occurs spontaneously or from seeded reactions. Comparison of these spectra with those of amyloid fibrils extracted from patients with dialysis-related amyloidosis revealed an identical amide I' absorbance maximum, suggestive of a characteristic and conserved amyloid fold. Our results endorse the relevance of biophysical studies for the investigation of the molecular mechanisms of β₂-microglobulin fibrillogenesis, knowledge about which may inform understanding of the pathobiology of this protein.

Received for publication, December 19, 2007 , and in revised form, March 10, 2008.

^* This work was supported by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and additional references.

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¹ Current address: Dept. of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.

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² To whom correspondence should be addressed: Astbury Centre for Structural Molecular Biology, Garstang Bldg., University of Leeds, Leeds LS2 9JT, UK. Tel.: 0113-343-3170; Fax: 0113-343-7486; E-mail: s.e.radford{at}leeds.ac.uk.

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