Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation

Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation

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 express...

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Bibliographic Details
Published in:Biomolecules (Basel, Switzerland) Vol. 11; no. 3; p. 411
Main Authors: Wasana Jayaweera, Sanduni, Surano, Solmaz, Pettersson, Nina, Oskarsson, Elvira, Lettius, Lovisa, Gharibyan, Anna L, Anan, Intissar, Olofsson, Anders
Format: Journal Article
Language:English
Published: Switzerland MDPI 10-03-2021
MDPI AG
Subjects:
amylin
amyloid
diabetes
IAPP
islet amyloid polypeptide
thioflavin T
transthyretin
TTR
islet amyloid polypeptide
TTR
amyloid
transthyretin
IAPP
amylin
thioflavin T
diabetes
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Summary: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.
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ISSN:2218-273X
2218-273X
DOI:10.3390/biom11030411