Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Department of Chemistry and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Nat Commun. 2018 Oct 30;9(1):4517. doi: 10.1038/s41467-018-06761-6.
All amyloid fibrils contain a cross-β fold. How this structure differs in fibrils formed from proteins associated with different diseases remains unclear. Here, we combine cryo-EM and MAS-NMR to determine the structure of an amyloid fibril formed in vitro from β-microglobulin (βm), the culprit protein of dialysis-related amyloidosis. The fibril is composed of two identical protofilaments assembled from subunits that do not share βm's native tertiary fold, but are formed from similar β-strands. The fibrils share motifs with other amyloid fibrils, but also contain unique features including π-stacking interactions perpendicular to the fibril axis and an intramolecular disulfide that stabilises the subunit fold. We also describe a structural model for a second fibril morphology and show that it is built from the same subunit fold. The results provide insights into the mechanisms of fibril formation and the commonalities and differences within the amyloid fold in different protein sequences.
所有的淀粉样纤维都包含一个交叉-β折叠。但是，由不同疾病相关蛋白形成的纤维中，这种结构有何不同仍不清楚。在这里，我们结合冷冻电镜和 MAS-NMR 来确定由β-微球蛋白（βm）形成的淀粉样纤维的结构，βm 是透析相关淀粉样变性的罪魁祸首蛋白。纤维由两个相同的原丝组成，原丝由不具有βm 天然三级折叠的亚基组装而成，但由相似的β-折叠组成。这些纤维与其他淀粉样纤维具有共同的特征，但也包含独特的特征，包括垂直于纤维轴的π-堆积相互作用和稳定亚基折叠的分子内二硫键。我们还描述了第二种纤维形态的结构模型，并表明它是由相同的亚基折叠构成的。这些结果为纤维形成的机制以及不同蛋白质序列中淀粉样折叠的共性和差异提供了深入了解。
