High-resolution Crystal Structure of β2-Microglobulin Formed at pH 7.0

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

Journal of Biochemistry, 142(3), 413-419 (2007)

β2-Microglobulin (β2-m), a light chain of the major histocompatibility complex class I, forms amyloid fibrils in patients undergoing long-term hemodialysis, causing dialysis-related amyloidosis. Based on a comparison of the X-ray structure obtained at pH 5.7 and that of β2-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 β2-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 β2-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 β-bulge in strand D into a contiguous β-strand is not unique to the crystals formed under slightly acidic conditions. In other words, although the formation of β2-m fibrils was enhanced under acidic conditions, it remains unknown if it is related to the increased propensity for the disappearance of the β-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.

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