Wulff Melanie, Baumann Monika, Thümmler Anka, Yadav Jay K, Heinrich Liesa, Knüpfer Uwe, Schlenzig Dagmar, Schierhorn Angelika, Rahfeld Jens-Ulrich, Horn Uwe, Balbach Jochen, Demuth Hans-Ulrich, Fändrich Marcus
Institute for Pharmaceutical Biotechnologie, Ulm University, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
Institute of Physics, Martin Luther University Halle-Wittenberg, Betty-Heimann-Strasse 7, 06120, Halle (Saale), Germany.
Angew Chem Int Ed Engl. 2016 Apr 11;55(16):5081-4. doi: 10.1002/anie.201511099. Epub 2016 Mar 11.
N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Aβ peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the N terminus of the unmodified peptide protects Aβ fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates.
N 端截短和焦谷氨酸（pE）形成是阿尔茨海默病中 Aβ 肽自然发生的化学修饰。我们在此表明，这两种修饰显著缩短了原纤维长度并降低了原纤维热解折叠的转变中点，但它们并未实质性地扰乱纤维状肽的构象。这一观察结果表明，未修饰肽的 N 端可保护 Aβ 原纤维免受机械应力和断裂影响，并解释了 pE 修饰肽形成小的且特别有毒聚集体的高倾向。
