TY - JOUR
T1 - Conformational preferences of the amylin nucleation site in SDS micelles
T2 - An NMR study
AU - Mascioni, Alessandro
AU - Porcelli, Fernando
AU - Ilangovan, Udayar
AU - Ramamoorthy, Ayyalusamy
AU - Veglia, Gianluigi
PY - 2003/5/1
Y1 - 2003/5/1
N2 - Human islet amyloid polypeptide (hIAPP), or amylin, is a 37 amino acid hormone secreted by pancreatic β-cells. hIAPP constitutes ∼90% of the amyloid deposits found in type II diabetic patients. It has been shown that the central region of the peptide (hIAPP20-29) constitutes the nucleation site for the amyloidogenic process with F23 playing a key role in the formation of the β-pleated structures. In addition, it has been proposed that an important stage in the cytotoxicity of hIAPP is its interaction with the β-cell membranes. As a first step toward the characterization of the interaction of hIAPP with cell membranes, we determined conformational preferences of hIAPP20-29 in membrane-mimicking environments. We found that upon interacting with negatively charged micelles, the dominant conformation of hIAPP20-29 is a distorted type I β-turn centered on residues F23 and G24, with F23, A25, and I26 forming a small hydrophobic cluster that may facilitate the interaction of this peptide with the membrane bilayer. Moreover, we were able to elucidate the topological orientation of the peptide that is absorbed on the micelle surface, with the hydrophobic cluster oriented toward the hydrocarbon region of the micelles and both N- and C-termini exposed to the solvent.
AB - Human islet amyloid polypeptide (hIAPP), or amylin, is a 37 amino acid hormone secreted by pancreatic β-cells. hIAPP constitutes ∼90% of the amyloid deposits found in type II diabetic patients. It has been shown that the central region of the peptide (hIAPP20-29) constitutes the nucleation site for the amyloidogenic process with F23 playing a key role in the formation of the β-pleated structures. In addition, it has been proposed that an important stage in the cytotoxicity of hIAPP is its interaction with the β-cell membranes. As a first step toward the characterization of the interaction of hIAPP with cell membranes, we determined conformational preferences of hIAPP20-29 in membrane-mimicking environments. We found that upon interacting with negatively charged micelles, the dominant conformation of hIAPP20-29 is a distorted type I β-turn centered on residues F23 and G24, with F23, A25, and I26 forming a small hydrophobic cluster that may facilitate the interaction of this peptide with the membrane bilayer. Moreover, we were able to elucidate the topological orientation of the peptide that is absorbed on the micelle surface, with the hydrophobic cluster oriented toward the hydrocarbon region of the micelles and both N- and C-termini exposed to the solvent.
KW - Amylin
KW - Human islet amyloid polypeptide
KW - Micelles
KW - Orientation
KW - Solution NMR
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U2 - 10.1002/bip.10305
DO - 10.1002/bip.10305
M3 - Article
C2 - 12717720
AN - SCOPUS:0038374923
VL - 69
SP - 29
EP - 41
JO - Biopolymers
JF - Biopolymers
SN - 0006-3525
IS - 1
ER -