Dataset Information

Dynamic alpha-helix structure of micelle-bound human amylin.

ABSTRACT: Amylin is an endocrine hormone that regulates metabolism. In patients afflicted with type 2 diabetes, amylin is found in fibrillar deposits in the pancreas. Membranes are thought to facilitate the aggregation of amylin, and membrane-bound oligomers may be responsible for the islet beta-cell toxicity that develops during type 2 diabetes. To better understand the structural basis for the interactions between amylin and membranes, we determined the NMR structure of human amylin bound to SDS micelles. The first four residues in the structure are constrained to form a hairpin loop by the single disulfide bond in amylin. The last nine residues near the C terminus are unfolded. The core of the structure is an alpha-helix that runs from about residues 5-28. A distortion or kink near residues 18-22 introduces pliancy in the angle between the N- and C-terminal segments of the alpha-helix. Mobility, as determined by (15)N relaxation experiments, increases from the N to the C terminus and is strongly correlated with the accessibility of the polypeptide to spin probes in the solution phase. The spin probe data suggest that the segment between residues 5 and 17 is positioned within the hydrophobic lipid environment, whereas the amyloidogenic segment between residues 20 and 29 is at the interface between the lipid and solvent. This orientation may direct the aggregation of amylin on membranes, whereas coupling between the two segments may mediate the transition to a toxic structure.

SUBMITTER: Patil SM

PROVIDER: S-EPMC2673267 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Dynamic alpha-helix structure of micelle-bound human amylin.

Patil Sharadrao M SM Xu Shihao S Sheftic Sarah R SR Alexandrescu Andrei T AT

The Journal of biological chemistry 20090224 18

Amylin is an endocrine hormone that regulates metabolism. In patients afflicted with type 2 diabetes, amylin is found in fibrillar deposits in the pancreas. Membranes are thought to facilitate the aggregation of amylin, and membrane-bound oligomers may be responsible for the islet beta-cell toxicity that develops during type 2 diabetes. To better understand the structural basis for the interactions between amylin and membranes, we determined the NMR structure of human amylin bound to SDS micelle ...[more]

PMID: 19244249

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Project description:The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

Dataset Information

Dynamic alpha-helix structure of micelle-bound human amylin.

Publications

Dynamic alpha-helix structure of micelle-bound human amylin.

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