1-2-oleoylphosphatidylcholine and Protein-Aggregation--Pathological

Interactions between superoxide dismutase-1 (SOD1) and lipid membranes might be directly involved in the toxicity and intercellular propagation of aggregated SOD1 in amyotrophic lateral sclerosis (ALS), but the chemical details of lipid-SOD1 interactions and their effects on SOD1 aggregation remain unclear. This paper determined the rate and mechanism of nucleation of fibrillar apo-SOD1 catalyzed by liposomal surfaces with identical hydrophobic chains (RCH

Topics: Amyotrophic Lateral Sclerosis; Humans; Hydrophobic and Hydrophilic Interactions; Liposomes; Phosphatidylcholines; Protein Aggregation, Pathological; Recombinant Proteins; Saccharomyces cerevisiae; Superoxide Dismutase-1; Surface Properties

Human islet amyloid polypeptide (hIAPP) is a 37-residue peptide hormone, which upon misfolding changes from the physiologically active monomer into pathological amyloid fibril aggregates in the pancreas of type 2 diabetes mellitus patients. During this process, the insulin-producing pancreatic β-cells are damaged; however, the underlying mechanism of this mode of cytotoxicity remains elusive. It is known that anionic lipids accelerate amyloid fibril formation, implicating the importance of the cellular membrane in the process, and that a pH close to the level in the β-cell secretory granules (pH 5.5) inhibits amyloid fibril formation. Using all-atom molecular dynamics simulations, we have investigated the membrane-associated monomer state of α-helical hIAPP, analyzed specific interactions of hIAPP with a mixed anionic-zwitterionic lipid membrane and examined the influence of pH on the structure and dynamics of hIAPP and its interaction with the membrane. We find that hIAPP primarily interacts with the membrane by forming favorable interactions between anionic lipids and the positively charged residues in the N-terminal part of the peptide. Rationalizing experimental findings, the simulations show that the N-terminal part of the peptide interacts with the membrane in the lipid headgroup region. At neutral pH, the C-terminal part of the peptide, which contains the residues that initiate fibril formation, displays a highly dynamic, unfolded state, which interacts with the membrane significantly less than the N-terminal part. Such an unfolded form can be proposed to contribute to the acceleration of fibril formation. At low pH, protonation of His18 mediates a stronger interaction of the C-terminal part with the membrane, resulting in the immobilization of the C-terminal part on the membrane surface that might constitute a mechanism by which low pH inhibits fibril formation.

Topics: Cell Membrane; Histidine; Humans; Hydrogen-Ion Concentration; Islet Amyloid Polypeptide; Kinetics; Models, Molecular; Molecular Dynamics Simulation; Peptide Fragments; Phosphatidylcholines; Phosphatidylserines; Protein Aggregation, Pathological; Protein Conformation; Protein Interaction Domains and Motifs; Protein Stability; Protein Structure, Tertiary; Protein Unfolding; Solubility; Unilamellar Liposomes