Limits...
Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.

Jiang P, Xu W, Mu Y - PLoS Comput. Biol. (2009)

Bottom Line: The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly.The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies.Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20-29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20-29 fragments aggregate into partially ordered beta-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel beta-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

Show MeSH
Secondary structure propensity of residues in rIAPP20–29 and hIAPP20–29.The secondary structures are assessed by DSSP package.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2663790&req=5

pcbi-1000357-g005: Secondary structure propensity of residues in rIAPP20–29 and hIAPP20–29.The secondary structures are assessed by DSSP package.

Mentions: To investigate the roles that residues play in aggregation, secondary structure propensity (SSP) for the ten residues are analyzed (Figure 5). It is obvious that three hydrophobic residues A25, I26, and L27 in hIAPP20–29 show high propensity for β-structures. The hydrophobic region (residues 25–27) is considered to be the core part of β-sheets for fragment hIAPP20–29 by experiments [57],[58]. The terminal residues (S20, N21, and S29) are generally unstructured, as their preferences for any of the three sorts of secondary structures are very low. Residues N22, F23, and G24 show high propensity for turn/bend. This may be due to the higher backbone flexibility of G24, and the side chain of F23 can be helpful for stabilizing turn/bend structures. The whole hIAPP20–29 sequence shows a rather low propensity for helical structures. In the presence of lipid (Figure 5 C), the probabilities of residues 22–24 taking turn/bend structures are reduced by approximately 10%, and their probabilities for β-sheets are increased contrastively. Moreover, fewer occurrences of β-hairpin strands are found in the presence of lipid molecule. Consequently, a role of lipid molecule in the aggregation process is disclosed that it prevents peptide from the formation of monomeric hairpin structure and helps the peptide stay in extended conformation. Compared to hIAPP, rIAPP fragment shows a similar propensity for turn/bend in residues 22–24, but β-structure possibilities of the whole sequence greatly decrease with only those of V27 and L28 remaining a relatively high level. Single mutation I27V slightly reduces ability of hIAPP20–29 [34] to form amyloid fibrils probably because that a valine residue has a nearly same hydrophobicity and SSP as an isoleucine residue does.


Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.

Jiang P, Xu W, Mu Y - PLoS Comput. Biol. (2009)

Secondary structure propensity of residues in rIAPP20–29 and hIAPP20–29.The secondary structures are assessed by DSSP package.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663790&req=5

pcbi-1000357-g005: Secondary structure propensity of residues in rIAPP20–29 and hIAPP20–29.The secondary structures are assessed by DSSP package.
Mentions: To investigate the roles that residues play in aggregation, secondary structure propensity (SSP) for the ten residues are analyzed (Figure 5). It is obvious that three hydrophobic residues A25, I26, and L27 in hIAPP20–29 show high propensity for β-structures. The hydrophobic region (residues 25–27) is considered to be the core part of β-sheets for fragment hIAPP20–29 by experiments [57],[58]. The terminal residues (S20, N21, and S29) are generally unstructured, as their preferences for any of the three sorts of secondary structures are very low. Residues N22, F23, and G24 show high propensity for turn/bend. This may be due to the higher backbone flexibility of G24, and the side chain of F23 can be helpful for stabilizing turn/bend structures. The whole hIAPP20–29 sequence shows a rather low propensity for helical structures. In the presence of lipid (Figure 5 C), the probabilities of residues 22–24 taking turn/bend structures are reduced by approximately 10%, and their probabilities for β-sheets are increased contrastively. Moreover, fewer occurrences of β-hairpin strands are found in the presence of lipid molecule. Consequently, a role of lipid molecule in the aggregation process is disclosed that it prevents peptide from the formation of monomeric hairpin structure and helps the peptide stay in extended conformation. Compared to hIAPP, rIAPP fragment shows a similar propensity for turn/bend in residues 22–24, but β-structure possibilities of the whole sequence greatly decrease with only those of V27 and L28 remaining a relatively high level. Single mutation I27V slightly reduces ability of hIAPP20–29 [34] to form amyloid fibrils probably because that a valine residue has a nearly same hydrophobicity and SSP as an isoleucine residue does.

Bottom Line: The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly.The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies.Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20-29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20-29 fragments aggregate into partially ordered beta-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel beta-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

Show MeSH