Dataset Information

Effect of proline mutations on the monomer conformations of amylin.

ABSTRACT: The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic ?-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate ?-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various ?-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long ?-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit ? conformations and stabilize the ?-helical conformation. Fewer substitutions do not have a significant inhibiting effect.

SUBMITTER: Chiu CC

PROVIDER: S-EPMC3762349 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Effect of proline mutations on the monomer conformations of amylin.

Chiu Chi-cheng CC Singh Sadanand S de Pablo Juan J JJ

Biophysical journal 20130901 5

The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic β-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three ...[more]

PMID: 24010666

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Project description:The amyloid aggregation of human islet amyloid polypeptide (hIAPP) is associated with pancreatic β-cell death in type 2 diabetes. The S20G substitution of hIAPP (hIAPP(S20G)), found in Japanese and Chinese people, is more amyloidogenic and cytotoxic than wild-type hIAPP. Rat amylin (rIAPP) does not have aggregation propensity or cytotoxicity. Mounting evidence suggests that soluble low-molecular-weight amyloid oligomers formed during early aggregation are more cytotoxic than mature fibrils. The self-assembly dynamics and oligomeric conformations remain unknown because the oligomers are heterogeneous and transient. The molecular mechanism of sequence-variation rendering dramatically different aggregation propensity and cytotoxicity is also elusive. Here, we investigate the oligomerization dynamics and conformations of amyloidogenic hIAPP, hIAPP(S20G), and non-amyloidogenic rIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our simulation results demonstrated that all three monomeric amylin peptides mainly adopted an unstructured formation with partial dynamical helices near the N-terminus. Relatively transient β-hairpins were more abundant in hIAPP and hIAPP(S20G) than in rIAPP. The S20G-substituting mutant of hIAPP altered the turn region of the β-hairpin motif, resulting in more hydrophobic residue-pairwise contacts within the β-hairpin. Oligomerization dynamic investigation revealed that all three peptides spontaneously accumulated into helix-populated oligomers. The conformational conversion to form β-sheet-rich oligomers was only observed in hIAPP and hIAPP(S20G). The population of high-β-sheet-content oligomers was enhanced by S20G substitution. Interestingly, both hIAPP and hIAPP(S20G) could form β-barrel formations, and the β-barrel propensity of hIAPP(S20G) was three times larger than that of hIAPP. No β-sheet-rich or β-barrel formations were observed in rIAPP. Our direct observation of the correlation between β-barrel oligomer formation and cytotoxicity suggests that β-barrels might play a critically important role in the cytotoxicity of amyloidosis.

Dataset Information

Effect of proline mutations on the monomer conformations of amylin.

Publications

Effect of proline mutations on the monomer conformations of amylin.

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