# Effect of Copper-Catalyzed Oxidation on the Aggregation of the Islet Amyloid Polypeptide

## TL;DR

This study explores how copper-induced oxidation affects the aggregation of a peptide linked to type 2 diabetes, revealing that oxidation changes the type of aggregates formed.

## Contribution

The study reveals how copper-mediated oxidation alters IAPP aggregation pathways through residue-specific modifications.

## Key findings

- Oxidation targets residues 20–29 of IAPP, reducing amyloid fibril formation and promoting amorphous aggregates.
- The H18A IAPP variant shows broader oxidation site distribution and altered fibril formation due to lack of histidine.
- Copper-induced oxidation provides mechanistic insights into IAPP aggregation in type 2 diabetes.

## Abstract

The islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone secreted by pancreatic β-cells that is known to aggregate into amyloid fibrils. These fibrils accumulate in the pancreatic islets of individuals afflicted with type 2 diabetes and are implicated in β-cell dysfunction. Metal ions such as copper and zinc are known to modulate IAPP fibrillization, yet the role of metal-induced oxidative modifications in this process remains largely unexplored. This study examines the non-enzymatic post-translational oxidation of IAPP and its effects on aggregation using the biologically relevant Cu/O2/ascorbate system. Mass spectrometry identified residues within the amyloidogenic region (residues 20–29) as the primary targets of oxidation. These oxidative modifications impaired the formation of cross-β-sheet amyloid fibrils and promoted the accumulation of amorphous aggregates. The H18A IAPP derivative, lacking the key metal-binding histidine, was also examined to assess the impact of sequence variation on oxidation and aggregation. Copper-mediated oxidation of H18A resulted in a broader distribution of oxidation sites and impacts fibril formation. These findings provide preliminary mechanistic insights into copper-induced oxidation and its impact on IAPP aggregation pathways.