The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosis

Ganoderma lucidum is a valuable medicinal herbal which has been reported to prevent type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum, namely, FYGL, has been demonstrated to inhibit the amyloidosis of human islet amyloid polypeptide (hIAPP) previously by our lab. However, the effective active components and the mechanisms of FYGL in inhibiting hIAPP amyloidosis are unknown. To identify the effective active components, different components from FYGL were isolated: the polysaccharide FYGL-1, the proteoglycans of FYGL-2 and FYGL-3. We further separated and sequenced the protein moieties of FYGL-2 and FYGL-3, namely, FYGL-2-P and FYGL-3-P, respectively, and compared their abilities to inhibit hIAPP amyloidosis, and systematically explored the inhibitory mechanisms by spectroscopy, microscopy and molecular dynamic simulation methods. Results showed that the protein moieties of FYGL played essential roles in inhibiting hIAPP amyloidosis. The strong, specific, and enthalpy-driven interaction by π-π stacking and electrostatic forces between hIAPP and FYGL-3-P dramatically inhibited hIAPP amyloidosis. These results suggested that FYGL-3-P had enormous potential to prevent hIAPP misfolding-induced diabetes and structurally helped researchers to seek or design inhibitors against polypeptide amyloidosis.