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

• Final Report Year: 2023

Final Report Abstract

We have shown that hIAPP fibrils adopt a topology that is similar to the recently determined cryo-EM structures. We observe only a single set of resonances indicating a high degree of structural homogeneity. In contrast to the cryo-EM structure, we observe a structured N- terminus. We have characterized the conformation of the N-terminus using MD simulations, and have found that a mutant that is lacking the disulfide bond at the N-terminus (hIAPPC2S,C7S) adopts a more extended conformation at the N-terminus in the amyloid fibril. The disulfide bond in the wt-hIAPP peptide induces a loop in the fibril structure which occludes residues 10- 18 in the second β-sheet and thus inhibits the fibril seeding reaction.

Publications

• Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice. Scientific Reports, 8(1).
  Franko, Andras; Rodriguez, Camargo Diana C.; Böddrich, Annett; Garg, Divita; Rodriguez, Camargo Andres; Rathkolb, Birgit; Janik, Dirk; Aichler, Michaela; Feuchtinger, Annette; Neff, Frauke; Fuchs, Helmut; Wanker, Erich E.; Reif, Bernd; Häring, Hans-Ulrich; Peter, Andreas & Hrabě, de Angelis Martin
  
• hIAPP forms toxic oligomers in plasma. Chemical Communications, 54(43), 5426-5429.
  Rodriguez, Camargo Diana C.; Garg, Divita; Buday, Katalin; Franko, Andras; Rodriguez, Camargo Andres; Schmidt, Fabian; Cox, Sarah J.; Suladze, Saba; Haslbeck, Martin; Mideksa, Yonatan G.; Gemmecker, Gerd; Aichler, Michaela; Mettenleiter, Gabriele; Schulz, Michael; Walch, Axel Karl; Hrabě, de Angelis Martin; Feige, Matthias J.; Sierra, Cesar A.; Conrad, Marcus ... & Reif, Bernd
  
• Small molecule induced toxic human-IAPP species characterized by NMR. Chemical Communications, 56(86), 13129-13132.
  Cox, Sarah J.; Rodriguez, Camargo Diana C.; Lee, Young-Ho; Dubini, Romeo C. A.; Rovó, Petra; Ivanova, Magdalena I.; Padmini, Vediappen; Reif, Bernd & Ramamoorthy, Ayyalusamy
  
• Conformational Tuning of Amylin by Charged Styrene-Maleic-Acid Copolymers. Journal of Molecular Biology, 434(2), 167385.
  Sahoo, Bikash R.; Souders, Christopher L.; Watanabe-Nakayama, Takahiro; Deng, Zhou; Linton, Hunter; Suladze, Saba; Ivanova, Magdalena I.; Reif, Bernd; Ando, Toshio; Martyniuk, Christopher J. & Ramamoorthy, Ayyalusamy