Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis

Figure 3

Roles of sulfated GAGs in IAPP amyloidogenesis. (a) Representative structure of heparin or heparan sulfate composed of glucuronic acid (GlcA) linked to glucosamine (GlcN) disaccharide repeating subunit. R₁ could be –H or – whereas could be –H, –, or –COCH₃. (b) Schematic representation of the postulated mechanism by which sulfated GAGs might promote IAPP amyloid formation. The positively charged N-terminal domain of IAPP binds to the sulfate moieties of GAGs by means of electrostatic interactions. This binding event triggers the formation of a α-helix (represented as a cylinder). This generates a high local concentration of peptide on the GAG scaffold that drives the association of IAPP amyloidogenic C-terminal segment, which has a high propensity to adopt a β-sheet (represented as an arrow). This drastically accelerates the formation of β-sheet rich assemblies.

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