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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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Schematic representation of misfolding/aggregation mechanism of hIAPP.Left: Helix-coil structure for normal function; Middle: aggregation-prone β-rich monomers; Right: early putative toxic dimers (Dupuis et al. JACS 2011). The question mark indicates the hairpins may further form cylindrin-like toxic oligomers, modeled from the cylindrical barrel of an amyloid peptide (PDB id: 3SGR) (Laganowsky et al. Science 2012). The isomerization symbol indicates that at some, as yet unknown size, the β-strand aggregates must rearrange to the β-sheet aggregates found in the fibrils. N-terminus is indicated by red ball, residues 23–29 in the “mutation region” are in red. In the β-hairpin, residues 19S-20S-21N-22N form a turn and residues 11–19 and 23–33 form two β-strands.
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pcbi-1003211-g007: Schematic representation of misfolding/aggregation mechanism of hIAPP.Left: Helix-coil structure for normal function; Middle: aggregation-prone β-rich monomers; Right: early putative toxic dimers (Dupuis et al. JACS 2011). The question mark indicates the hairpins may further form cylindrin-like toxic oligomers, modeled from the cylindrical barrel of an amyloid peptide (PDB id: 3SGR) (Laganowsky et al. Science 2012). The isomerization symbol indicates that at some, as yet unknown size, the β-strand aggregates must rearrange to the β-sheet aggregates found in the fibrils. N-terminus is indicated by red ball, residues 23–29 in the “mutation region” are in red. In the β-hairpin, residues 19S-20S-21N-22N form a turn and residues 11–19 and 23–33 form two β-strands.

Mentions: In summary, there are compelling genetic, biochemical, cellular and animal data to support both natural biological functions for hIAPP and a toxic role of hIAPP leading to β-cell death [14], [34], [37], [104]–[107]. Combining these functional data with our structural models of four IAPP variants, we put forth the structure-activity relationship (SAR) that the helix-coil conformations are responsible for the normal hormone function of IAPP; and that β-rich conformations of IAPP may be linked to β-rich aggregation and contribute, along with other mechanisms, to the toxicity of IAPP. While the former might be realized by binding of the helix-coil conformers to AMY receptor, the latter might be due to the formation of toxic β-rich oligomers and amyloid fibrils leading to β-cell death. This SAR scheme is summarized in Figure 7. Our SAR can give insights into the rational design of drugs to combat Type II Diabetes, with drugs that either destabilize the pathological conformations and/or promote the formation of the physiologically active conformations. These drugs could come in the form of small molecules, or be peptide based. Ideally, one could design an IAPP variant that retains the functional role of hIAPP, but does not have the same tendency as hIAPP to misfold and aggregate (such as pramlintide), and that furthermore inhibits the aggregation of wild type hIAPP. This drug would not only enhance insulin-sensitivity (like pramlintide), but also preserve β-cells by preventing aggregation.


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)

Schematic representation of misfolding/aggregation mechanism of hIAPP.Left: Helix-coil structure for normal function; Middle: aggregation-prone β-rich monomers; Right: early putative toxic dimers (Dupuis et al. JACS 2011). The question mark indicates the hairpins may further form cylindrin-like toxic oligomers, modeled from the cylindrical barrel of an amyloid peptide (PDB id: 3SGR) (Laganowsky et al. Science 2012). The isomerization symbol indicates that at some, as yet unknown size, the β-strand aggregates must rearrange to the β-sheet aggregates found in the fibrils. N-terminus is indicated by red ball, residues 23–29 in the “mutation region” are in red. In the β-hairpin, residues 19S-20S-21N-22N form a turn and residues 11–19 and 23–33 form two β-strands.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003211-g007: Schematic representation of misfolding/aggregation mechanism of hIAPP.Left: Helix-coil structure for normal function; Middle: aggregation-prone β-rich monomers; Right: early putative toxic dimers (Dupuis et al. JACS 2011). The question mark indicates the hairpins may further form cylindrin-like toxic oligomers, modeled from the cylindrical barrel of an amyloid peptide (PDB id: 3SGR) (Laganowsky et al. Science 2012). The isomerization symbol indicates that at some, as yet unknown size, the β-strand aggregates must rearrange to the β-sheet aggregates found in the fibrils. N-terminus is indicated by red ball, residues 23–29 in the “mutation region” are in red. In the β-hairpin, residues 19S-20S-21N-22N form a turn and residues 11–19 and 23–33 form two β-strands.
Mentions: In summary, there are compelling genetic, biochemical, cellular and animal data to support both natural biological functions for hIAPP and a toxic role of hIAPP leading to β-cell death [14], [34], [37], [104]–[107]. Combining these functional data with our structural models of four IAPP variants, we put forth the structure-activity relationship (SAR) that the helix-coil conformations are responsible for the normal hormone function of IAPP; and that β-rich conformations of IAPP may be linked to β-rich aggregation and contribute, along with other mechanisms, to the toxicity of IAPP. While the former might be realized by binding of the helix-coil conformers to AMY receptor, the latter might be due to the formation of toxic β-rich oligomers and amyloid fibrils leading to β-cell death. This SAR scheme is summarized in Figure 7. Our SAR can give insights into the rational design of drugs to combat Type II Diabetes, with drugs that either destabilize the pathological conformations and/or promote the formation of the physiologically active conformations. These drugs could come in the form of small molecules, or be peptide based. Ideally, one could design an IAPP variant that retains the functional role of hIAPP, but does not have the same tendency as hIAPP to misfold and aggregate (such as pramlintide), and that furthermore inhibits the aggregation of wild type hIAPP. This drug would not only enhance insulin-sensitivity (like pramlintide), but also preserve β-cells by preventing aggregation.

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