Abstract
Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic islet β-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability of β-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined.
Highlights
Type 2 diabetes mellitus (T2DM) is classified as a proteinmisfolding disease and shares the debilitating consequences of misfolded and aggregated peptides and proteins with more than 20 other diseases, such as Alzheimer’s disease, Parkinson’s disease, and spongiform encephalopathy [1,2,3]
In T2DM, amyloid deposits were initially assumed to be composed of insulin; in 1987 two different groups discovered that the major component of islet amyloid is a 37-residue polypeptide pancreatic hormone [7, 8], initially named insulinoma amyloid peptide [9], diabetes-associated peptide [7], and islet amyloid polypeptide (IAPP) [8] or amylin [10]
This study showed that Human islet amyloid polypeptide (hIAPP) forms ion-channel-like structures in reconstituted membranes suggesting that these oligomeric hIAPP pores could insert in membranes and change their barrier properties
Summary
Type 2 diabetes mellitus (T2DM) is classified as a proteinmisfolding disease and shares the debilitating consequences of misfolded and aggregated peptides and proteins with more than 20 other diseases, such as Alzheimer’s disease, Parkinson’s disease, and spongiform encephalopathy [1,2,3]. As for all amyloid forming peptides, hIAPP undergoes a conformational transition from its nonfolded state to a β-sheet structure, which increases over time [28,29,30] This initial peptide conformational change is the key step leading to the formation of oligomers to highly ordered and insoluble amyloid fibrils. The second model for hIAPP fibrils was obtained by using X-ray crystallography and is based on steric zippers and on crystal structures that were obtained on segments 20–27 (NNFGAIL) and 29–33 (SSTNVG) of the peptide This model, similar to that obtained by solidstate NMR with the exception of atomic distances between β-sheet layers, suggests that a monomer of hIAPP has a hairpin structure consisting of two β-strands. These stacks of peptides associate themselves one on top of another, perpendicular to the fibril axis, to form the mature amyloid fibril [39]
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