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Journal of Biochemistry Advance Access originally published online on July 23, 2007
Journal of Biochemistry 2007 142(3):413-419; doi:10.1093/jb/mvm148
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© 2007 The Japanese Biochemical Society.

High-resolution Crystal Structure of ß2-Microglobulin Formed at pH 7.0{dagger}

Kentaro Iwata, Takanori Matsuura, Kazumasa Sakurai, Atsushi Nakagawa and Yuji Goto*

Institute for Protein Research, Osaka University, and CREST, Japan Science and Technology Agency, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan

*To whom correspondence should be addressed. Tel: +81-6-6879-8614, Fax: +81-6-6879-8616, E-mail: ygoto{at}protein.osaka-u.ac.jp

Received June 14, 2007; Accepted July 3, 2007


  Abstract

ß2-Microglobulin (ß2-m), a light chain of the major histocompatibility complex class I, forms amyloid fibrils in patients undergoing long-term haemodialysis, causing dialysis-related amyloidosis. Based on a comparison of the X-ray structure obtained at pH 5.7 and that of ß2-m in the histocompatibility complex, it has been proposed that the continuous D-strand observed in the crystal structure at pH 5.7 increases the propensity of ß2-m to self-associate via edge-to-edge interactions, thus initiating the formation of fibrils. To obtain further insight into the mechanism by which amyloid fibrils form, we determined the crystal structure of ß2-m at pH 7.0 at a resolution of up to 1.13 Å. The crystal structure at pH 7.0 was basically the same as that at pH 5.6, suggesting that the conversion of the ß-bulge in strand D into a contiguous ß-strand is not unique to the crystals formed under slightly acidic conditions. In other words, although the formation of ß2-m fibrils was enhanced under acidic conditions, it remains unknown if it is related to the increased propensity for the disappearance of the ß-bulge in strand D. We consider that the enhanced fibrillation is more directly coupled with the decreased stability leading to the increased propensity of exposing amyloidogenic regions.

Key Words: amyloid fibrils, ß-bulge, dialysis-related amyloidosis, ß2-microglobulin, X-ray crystallography

Abbreviations: ß2-m, ß2-microglobulin; NMR, nuclear magnetic resonance


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