The pressure and temperature perturbation approach reveals a whole variety of conformational substates of amyloidogenic hIAPP monitored by 2D NMR spectroscopy

• Published in: Biophysical chemistry 2019-11, Vol.254, p.106239-106239, Article 106239
• Main Authors: Beck Erlach, Markus, Kalbitzer, Hans Robert, Winter, Roland, Kremer, Werner
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amylin; Amyloid; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Fibrils; Humans; IAPP; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - metabolism; Molecular Dynamics Simulation; NMR; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Pressure; Protein Conformation; Substrate Specificity; Temperature
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/j.bpc.2019.106239

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 Aβ(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 Aβ). The N-terminal area of hIAPP around amino acid residues 3–20 displays large differences in pressure sensitivity compared to Aβ, 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 Aβ(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. [Display omitted] •Aim to understand the initial self-assembly of hIAPP•Pressure and temperature induced NMR derived chemical shift changes pinpoint to structurally important residues•Pressure and temperature dependencies reveal residues that seem to play an important role during aggregation•Results show that the initial self-assembly of hIAPP diplays strong differences in comparison to Aβ