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Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration.

ABSTRACT: While islet amyloid polypeptide (IAPP) aggregation is associated with ?-cell death in type-II diabetes (T2D), environmental elements of ?-cell granules - e.g. high concentrations of insulin and Zn(2+) - inhibit IAPP aggregation in healthy individuals. The inhibition by insulin is experimentally known, but the role of Zn(2+) is controversial as both correlations and anti-correlations at the population level are observed between T2D risk and the activity of a ?-cell specific zinc ion transporter, ZnT8. Since Zn(2+) concentration determines insulin oligomer equilibrium, we computationally investigated interactions of IAPP with different insulin oligomers and compared with IAPP homodimer formation. We found that IAPP binding with insulin oligomers competes with the formation of both higher-molecular-weight insulin oligomers and IAPP homodimers. Therefore, zinc deficiency due to loss-of-function ZnT8 mutations shifts insulin oligomer equilibrium toward zinc-free monomers and dimers, which bind IAPP monomers more efficiently compared to zinc-bound hexamers. The hetero-molecular complex formation prevents IAPP from self-association and subsequent aggregation, reducing T2D risk.

SUBMITTER: Nedumpully-Govindan P

PROVIDER: S-EPMC4316164 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration.

Nedumpully-Govindan Praveen P Ding Feng F

Scientific reports 20150204

While islet amyloid polypeptide (IAPP) aggregation is associated with β-cell death in type-II diabetes (T2D), environmental elements of β-cell granules - e.g. high concentrations of insulin and Zn(2+) - inhibit IAPP aggregation in healthy individuals. The inhibition by insulin is experimentally known, but the role of Zn(2+) is controversial as both correlations and anti-correlations at the population level are observed between T2D risk and the activity of a β-cell specific zinc ion transporter, ...[more]

PMID: 25649462

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Project description:The mechanosensitive channel of large conductance (MscL) is capable of transducing mechanical stimuli such as membrane tension into an electrochemical response. MscL provides a widely-studied model system for mechanotransduction and, more generally, for how bilayer mechanical properties regulate protein conformational changes. Much effort has been expended on the detailed experimental characterization of the molecular structure and biological function of MscL. However, despite its central significance, even basic issues such as the physiologically relevant oligomeric states and molecular structures of MscL remain a matter of debate. In particular, tetrameric, pentameric, and hexameric oligomeric states of MscL have been proposed, together with a range of detailed molecular structures of MscL in the closed and open channel states. Previous theoretical work has shown that the basic phenomenology of MscL gating can be understood using an elastic model describing the energetic cost of the thickness deformations induced by MscL in the surrounding lipid bilayer. Here, we generalize this elastic model to account for the proposed oligomeric states and hydrophobic shapes of MscL. We find that the oligomeric state and hydrophobic shape of MscL are reflected in the energetic cost of lipid bilayer deformations. We make quantitative predictions pertaining to the gating characteristics associated with various structural models of MscL and, in particular, show that different oligomeric states and hydrophobic shapes of MscL yield distinct membrane contributions to the gating energy and gating tension. Thus, the functional properties of MscL provide a signature of the oligomeric state and hydrophobic shape of MscL. Our results suggest that, in addition to the hydrophobic mismatch between membrane proteins and the surrounding lipid bilayer, the symmetry and shape of the hydrophobic surfaces of membrane proteins play an important role in the regulation of protein function by bilayer membranes.

Dataset Information

Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration.

Publications

Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration.

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