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Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-3430-3101
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2021 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 411Article in journal, Editorial material (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
MDPI, 2021. Vol. 11, no 3, article id 411
Keywords [en]
IAPP, TTR, amylin, amyloid, diabetes, islet amyloid polypeptide, thioflavin T, transthyretin
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:umu:diva-182798DOI: 10.3390/biom11030411ISI: 000633423800001PubMedID: 33802170Scopus ID: 2-s2.0-85103862637OAI: oai:DiVA.org:umu-182798DiVA, id: diva2:1549240
Funder
The Swedish Brain Foundation, FO2018-0334Stiftelsen Olle Engkvist Byggmästare, 199-0469Stiftelsen Gamla Tjänarinnor, 2018-00718Available from: 2021-05-05 Created: 2021-05-05 Last updated: 2023-09-05Bibliographically approved

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Jayaweera, Sanduni WasanaSurano, SolmazPettersson, NinaGharibyan, Anna L.Anan, IntissarOlofsson, Anders

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Jayaweera, Sanduni WasanaSurano, SolmazPettersson, NinaGharibyan, Anna L.Anan, IntissarOlofsson, Anders
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Department of Medical Biochemistry and BiophysicsWallenberg Centre for Molecular Medicine at Umeå University (WCMM)
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