Structural Characterization of hIAPP aggregates using MAS solid-state NMR

• Applicant: Professor Dr. Bernd Reif
• Subject Area: Structural Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400866545

The goal of the project is the determination of the structure of hIAPPox and hIAPPred fibrils at high resolution using MAS solid-state NMR. We will focus in particular on the N-terminal region of the peptide hormone to investigate the role of the disulfide bridge in the aggregate structure, and to understand its function in seeding and redox balancing. Seeding will be done with de novo generated fibrils as well as with ex vivo aggregate material. In addition to the pure hIAPPred and hIAPPox fibrils, we will produce hIAPP fibril samples that are obtained using a redox buffer that yields a 1:1 mixture of hIAPPred and hIAPPox in solution prior to aggregation. We aim to find out if only hIAPPred peptides are incorporated into the fibril, and how hIAPPox perturbs the fibril structure. In addition to static structures, we will investigate the dynamics of proteins in these amyloid fibrils, and aim to correlate local structural parameters to the thermodynamic stability of fibril structure. We expect that these experiments will allow to obtain a better mechanistic understanding of seeding and cross-seeding of an amyloid fibril.

• DFG Programme: Research Grants