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.
School of Biological Sciences, Nanyang Technological University, Singapore.
Ping
P
Jiang
Weixin
W
Xu
Yuguang
Y
Mu
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