Mechanisms of Transthyretin Inhibition of IAPP AmyloidFormation

• Main Authors: Sanduni Wasana Jayaweera, Solmaz Surano, Nina Pettersson, Elvira Oskarsson, Lovisa Lettius, Anna L. Gharibyan, Intissar Anan, Anders Olofsson
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Biomolecules
• Subjects: islet amyloid polypeptide; IAPP; amylin; amyloid; transthyretin; TTR
• Online Access: https://www.mdpi.com/2218-273X/11/3/411

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.