Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.
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.
Jiang
Ping
P
School of Biological Sciences, Nanyang Technological University, Singapore.
Xu
Weixin
W
Mu
Yuguang
Y
D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000648:ultrastructure*; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D008055:Lipids / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D008055:Lipids; D011392:Proline