Human Islet Amyloid Polypeptide Assembly: The Key Role of the 8–20 Fragment

Abstract

The aggregation of human islet amyloid polypeptide (hIAPP) has been closely associated with the pathogeny of type 2 diabetes mellitus (T2DM) and destruction of pancreatic islet β-cells. Several amyloidogenic domains within the hIAPP sequence capable of self-association have been identified. Among them is the 8–20 region of hIAPP, which has formed β-sheet fibrils despite being contained within an α-helical region of full-length hIAPP. To further understand the propensity of this region for self-assembly, two peptide fragments were compared, one consisting of the residues 8–20 (WT 8–20 ) and a mutant fragment with a His18Pro substitution (H18P 8–20 ). The conformational distribution and aggregation propensity of these peptides was determined using a combination of ion mobility mass spectrometry and atomic force microscopy. Our results reveal that the two peptide fragments have vastly differing assembly pathways. WT 8–20 produces a wide range of oligomers up to decamer whereas the H18P 8–20 mutant produces only low order oligomers. This study confirms the propensity of the 8–20 region to aggregate from its native α-helical structure into amyloid β-sheet oligomers and highlights the significance of the charged His18 in the aggregation process.