Department of Chemistry, Université du Québec à Montréal, Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), C.P. 8888, Montréal (Canada).
Angew Chem Int Ed Engl. 2015 Nov 23;54(48):14383-7. doi: 10.1002/anie.201507092. Epub 2015 Oct 6.
Amyloid deposition is a hallmark of many diseases, such as the Alzheimer's disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self-assembly. Recent studies have indicated that the formation of α-helical intermediates accelerates fibrillization, suggesting that these species are on-pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co-assembles with IAPP, we observed that helical species were off-pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis.
淀粉样蛋白沉积是许多疾病的标志，如阿尔茨海默病。许多淀粉样蛋白原性蛋白，包括与 2 型糖尿病相关的胰岛淀粉样多肽（IAPP），在天然状态下是无规卷曲的，需要经历构象重排，从而允许形成局部有序结构，以启动自组装。最近的研究表明，α-螺旋中间体的形成加速了纤维形成，这表明这些物种是淀粉样蛋白组装的途径上的。通过鉴定一种具有受限构象集合的 IAPP 衍生物，它与 IAPP 共同组装，我们观察到在均相环境中和存在脂质双层或糖胺聚糖的情况下，螺旋物种是偏离途径的。此外，阻止螺旋折叠增强了膜扰动和 IAPP 的细胞毒性，表明稳定螺旋基序是一种有前途的策略，可以防止与淀粉样蛋白形成相关的细胞退化。
