Erlach, Markus Beck and Kalbitzer, Hans Robert and Winter, Roland and Kremer, Werner (2019) The pressure and temperature perturbation approach reveals a whole variety of conformational substates of amyloidogenic hIAPP monitored by 2D NMR spectroscopy. BIOPHYSICAL CHEMISTRY, 254: 106239. ISSN 0301-4622, 1873-4200
Full text not available from this repository. (Request a copy)Abstract
The intrinsically disordered human islet amyloid polypeptide (hIAPP) is a 37 amino acid peptide hormone that is secreted by pancreatic beta cells along with glucagon and insulin. The glucose metabolism of humans is regulated by a balanced ratio of insulin and hIAPP. The disturbance of this balance can result in the development of type-2 diabetes mellitus (T2DM), whose pathogeny is associated by self-assembly induced aggregation and amyloid deposits of hIAPP into nanofibrils. Here, we report pressure- and temperature-induced changes of NMR chemical shifts of monomeric hIAPP in bulk solution to elucidate the contribution of conformational substates in a residue-specific manner in their role as molecular determinants for the initial self-assembly. The comparison with a similar peptide, the Alzheimer peptide A beta(1-40), which is leading to self-assembly induced aggregation and amyloid deposits as well, reveals that in both peptides highly homologous areas exist (Q10-L16 and N21-L27 in hIAPP and Q15-A21 and S26-I32 in A beta). The N-terminal area of hIAPP around amino acid residues 3-20 displays large differences in pressure sensitivity compared to A beta, pinpointing to a different structural ensemble in this sequence element which is of helical origin in hIAPP. Knowledge of the structural nature of the highly amyloidogenic hIAPP and the differences with respect to the conformational ensemble of A beta(1-40) will help to identify molecular determinants of self-assembly as well as cross-seeded assembly initiated aggregation and help facilitate the rational design of drugs for therapeutic use.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALPHA-HELICAL STATES; CHEMICAL-SHIFTS; POLYPEPTIDE IAPP; ISLET; PROTEIN; FIBRILLATION; DEPENDENCE; MECHANISM; IDENTIFICATION; AGGREGATION; IAPP; Amylin; Amyloid; NMR; Fibrils |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Dr. Hans Robert Kalbitzer |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2020 13:07 |
| Last Modified: | 24 Mar 2020 13:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25884 |
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