Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases. Issue 15 (2nd March 2021)

• Record Type: Journal Article
• Authors: Zhang, Yanxian; Zhang, Mingzhen; Liu, Yonglan; Zhang, Dong; Tang, Yijing; Ren, Baiping; Zheng, Jie
• Is Part Of: Journal of materials chemistry. Volume 9:Issue 15(2021)
• Page Start: 3300
• Page End: 3316
• Publication Date: 2021-03-02
• Subjects: Materials -- Periodicals; Chemistry, Analytic -- Periodicals; Biomedical materials -- Research -- Periodicals; 543.0284
• DOI: 10.1039/d0tb02958k
• Languages: English
• ISSNs: 2050-750X

Abstract

Abstract : In vitro cross-interactions between three different amyloid peptides of GNNQQNY, Aβ, and hIAPP demonstrate the pathological links between three different amyloid diseases of Alzheimer, type 2 diabetes, and Prion diseases. Abstract : Amyloid cross-seeding, as a result of direct interaction and co-aggregation between different disease-causative peptides, is considered as a main mechanism for the spread of the overlapping pathology across different cells and tissues between different protein-misfolding diseases (PMDs). Despite the biomedical significance of amyloid cross-seeding in amyloidogenesis, it remains a great challenge to discover amyloid cross-seeding systems and reveal their cross-seeding structures and mechanisms. Herein, we are the first to report that GNNQQNY – a short fragment from yeast prion protein Sup35 – can cross-seed with both amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form β-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric β-zippers, formed by the two β-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric β-zippers in a variety of GNNQQNY-Aβ and GNNQQNY-hIAPP assemblies also explains amyloid polymorphism. In addition, alteration of steric zipper formation by single-point mutations of GNNQQNY and interactions of GNNQQNY with different Aβ and hIAPP seeds leads to different amyloid cross-seeding efficiencies, further confirming the existence of cross-seeding barriers. This work offers a better structural-based understanding of amyloid cross-seeding mechanisms linked to different PMDs.