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Structural similarities and differences between amyloidogenic and non-amyloidogenic islet amyloid polypeptide (IAPP) sequences and implications for the dual physiological and pathological activities of these peptides.

Wu C, Shea JE - PLoS Comput. Biol. (2013)

Bottom Line: The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes.Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer.We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.

ABSTRACT
IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate and this process is linked to β-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes.

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Related in: MedlinePlus

Secondary structure propensities of the four IAPP variants at 300 K.Stardard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K.
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pcbi-1003211-g003: Secondary structure propensities of the four IAPP variants at 300 K.Stardard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K.

Mentions: The secondary structure propensities for the four peptides are shown in Figure 3. While all peptides show a high fraction of turn and coil structures (from 0.49 for hIAPP to 0.57 for rIAPP), consistent with the natively disordered structural nature of IDPs, there are nonetheless some striking differences between the amyloidogenic (human, cat) and non-amyloidogenic (rat, pig) sequences. In particular, while helicity is present in each peptide, the degree of helicity is much more pronounced for the non-amyloidogenic sequences (∼0.4 for pIAPP and rIAPP vs. ∼0.1 for cIAPP and hIAPP ). The trend for sheet structure is reversed, with low β-sheet content (∼0.03) for pIAPP and rIAPP and significantly larger content (∼0.4) for cIAPP and hIAPP.


Structural similarities and differences between amyloidogenic and non-amyloidogenic islet amyloid polypeptide (IAPP) sequences and implications for the dual physiological and pathological activities of these peptides.

Wu C, Shea JE - PLoS Comput. Biol. (2013)

Secondary structure propensities of the four IAPP variants at 300 K.Stardard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757079&req=5

pcbi-1003211-g003: Secondary structure propensities of the four IAPP variants at 300 K.Stardard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K.
Mentions: The secondary structure propensities for the four peptides are shown in Figure 3. While all peptides show a high fraction of turn and coil structures (from 0.49 for hIAPP to 0.57 for rIAPP), consistent with the natively disordered structural nature of IDPs, there are nonetheless some striking differences between the amyloidogenic (human, cat) and non-amyloidogenic (rat, pig) sequences. In particular, while helicity is present in each peptide, the degree of helicity is much more pronounced for the non-amyloidogenic sequences (∼0.4 for pIAPP and rIAPP vs. ∼0.1 for cIAPP and hIAPP ). The trend for sheet structure is reversed, with low β-sheet content (∼0.03) for pIAPP and rIAPP and significantly larger content (∼0.4) for cIAPP and hIAPP.

Bottom Line: The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes.Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer.We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California, United States of America.

ABSTRACT
IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate and this process is linked to β-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes.

Show MeSH
Related in: MedlinePlus