Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden.
Wallenberg Centre for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden.
Biomolecules. 2021 Mar 10;11(3):411. doi: 10.3390/biom11030411.
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.
胰岛淀粉样多肽（IAPP）由人胰腺中的β细胞产生，其淀粉样形成与 2 型糖尿病（T2DM）的发展有关。人血浆蛋白转甲状腺素（TTR）是一种众所周知的淀粉样蛋白抑制蛋白，有趣的是，它也在产生 IAPP 的β细胞中表达。在本研究中，我们研究了 TTR 干扰 IAPP 淀粉样形成的能力，包括其内在稳定性以及 TTR 稳定药物的影响。结果表明，TTR 可以延长 IAPP 淀粉样形成过程中的迟滞期并阻碍其延伸。我们还表明，干扰能力与 TTR 的热力学稳定性呈反比相关，而与动力学稳定性无关。此外，我们证明 TTR 干扰的能力在胰腺β细胞中含有 IAPP 的颗粒的低 pH 环境中也得以维持。然而，在中性和低 pH 条件下，添加 TTR 稳定药物会部分削弱其功效。总之，这些结果揭示了 TTR 介导的 IAPP 淀粉样形成抑制的机制，并强调了预防 T2DM 发病的潜在治疗靶点。
