透析アミロイドーシスの原因タンパク質がアミロイド線維形成を加速する仕組みを解明―化学合成タンパク質によりisoAsp修飾の影響を精密に実証―

2026-08-03 京都大学

β2-ミクログロブリンのisoAsp化は、迅速なアミロイド線維を引き起こす。（https://doi.org/10.1002/anie.7045464、CC-BY-NC-NDライセンスの下で公開

＜関連情報＞

• https://www.kyoto-u.ac.jp/ja/research-news/2026-08-03-2
• https://onlinelibrary.wiley.com/doi/10.1002/anie.7045464

翻訳後イソアスパラギン酸はβ2-ミクログロブリンにおけるアミロイド形成を促進する Post-Translational Isoaspartate Promotes Amyloid Formation in β2-Microglobulin

Ryuji Kawakami, Toshiki Takei, Masatomo So, Toshifumi Takao, Yoshinori Taguchi, Hironobu Hojo
Angewandte Chemie International Edition  Published: 08 June 2026
DOI:https://doi.org/10.1002/anie.7045464

ABSTRACT

β₂-Microglobulin (β2m) aggregation is central to dialysis-related amyloidosis (DRA), yet the molecular triggers underlying its fibrillogenesis remain incompletely defined. Among proposed mechanisms, isoaspartate (isoAsp) formation at Asn residues has been implicated but never directly tested due to synthetic inaccessibility. Here, we report the total chemical synthesis of β2m variants containing isoAsp at known in vivo hotspots, Asn¹⁷ and Asn⁴², enabling precise structural and functional interrogation. Remarkably, the isoAsp¹⁷-modified β2m exhibited greater fibril formation capacity than the pathogenic ΔN6-β2m variant, suggesting a previously underappreciated contribution of isoAsp¹⁷. Structural characterization was complemented by spectroscopic and TEM analyses, which demonstrated that isoAsp¹⁷ promotes fibril formation. Our findings provide the first direct experimental evidence that a spontaneous post-translational modification can initiate amyloidogenesis in β2m, redefining the molecular basis of DRA and highlighting isoAsp as a general driver of pathological protein aggregation.