| dc.description.abstract | Islet amyloid polypeptide (IAPP or amylin) is a 37-residue peptide secreted with insulin by beta cells in the islet of Langerhans. The aggregation of the peptide into either amyloid fibers or small oligomers has been implicated in the death of beta- cells during type 2 diabetes through its ability to disrupt the cellular membrane. While the structure of the mostly inert fibrillar form of IAPP has been investigated, the structural details of the highly toxic prefibrillar membrane-bound states of IAPP have been elusive. Previous research has indicated that the N-terminal region of the peptide (residues 1-19) is primarily responsible for the membrane disrupting effect
of the hIAPP peptide and induces membrane disruption to a similar extent as the full-length peptide without forming amyloid fibers upon binding to the membrane. The rIAPP1-19, which is both non-cytotoxic and non-amyloidogenic, differs from the hIAPP1-19 by only one amino acid residue: Arg18 in rIAPP1-19 and His18 in hIAPP1-19.
To elucidate the effect of this difference, we investigated the molecular interaction
of rIAPP1-19 and hIAPP1-19 with model cell membrane using sum frequency generation
(SFG) vibrational spectroscopy. Symmetric 1-palmitoyl-2-oleoyl-sn-glycero-3-
[Phospho-rac-(1-glycerol)] (POPG) was used as a model cell membrane in this study. It was found that, under our experimental conditions, the more toxic hIAPP1-
19 peptide tends to disrupt POPG/POPG bilayer and adopt a transmembrane
orientation with an angle of about 20o from the POPG bilayer normal at pH 7.3, while the less toxic rIAPP1-19 peptide binds to the POPG membrane surface with an angle
of about 70o from the bilayer normal and exerts no disruptive activity to the POPG
membrane. Deprotonating His18 in hIAPP1-19 reorients the peptide to the surface of the POPG/POPG bilayer. On the contrary, at more acidic environment (pH 5.5), hIAPP1-19 and rIAPP1-19 molecules were found to adopt anearly parallel orientation to the bilayer surface, with an orientation angle of about 65o (hIAPP1-19) and 80o (rIAPP1-19) from the bilayer normal, respectively.
Keywords: IAPP, hIAPP1-19, rIAPP1-19, Sum Frequency Generation (SFG), POPG/POPG
bilayer membranes. | en_US |
