title: Role of aromatic interactions in amyloid formation by islet amyloid polypeptide.
abstract: Aromatic-aromatic and aromatic-hydrophobic interactions have been proposed to play a role in amyloid formation by a range of polypeptides, including islet amyloid polypeptide (IAPP or amylin). IAPP is responsible for amyloid formation in patients with type 2 diabetes. The polypeptide is 37 residues long and contains three aromatic residues, Phe-15, Phe-23, and Tyr-37. The ability of all single aromatic to leucine mutants, all double aromatic to leucine mutants, and the triple leucine mutant to form amyloid were examined. Amyloid formation was almost twice as rapid for the F15L mutant as for the wild type but was almost 3-fold slower for the Y37L mutant and almost 2-fold slower for the F23L mutant. Amyloid fibrils formed from each of the single mutants were effective at seeding amyloid formation by wild-type IAPP, implying that the fibril structures are similar. The F15L/F23L double mutant has a larger effect than the F15L/Y37L double mutant on the rate of amyloid formation, even though a Y37L substitution has more drastic consequences in the wild-type background than does the F23L mutation, suggesting nonadditive effects between the different sites. The triple leucine mutant and the F23L/Y37L double mutant are the slowest to form amyloid. F15 has been proposed to make important contacts early in the aggregation pathway, but the data for the F15L mutant indicate that they are not optimal. A set of variants containing natural and unnatural amino acids at position 15, which were designed to conserve hydrophobicity, but alter α-helix and β-sheet propensity, were analyzed to determine the properties of this position that control the rate of amyloid formation. There is no correlation between β-sheet propensity at this position and the rate of amyloid formation, but there is a correlation with α-helical propensity.
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, USA.
authors.forename: Ling-Hsien
authors.initials: LH
authors.lastname: Tu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D007930:Leucine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020005:Propanols / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated
chemical_list: D058228:Islet Amyloid Polypeptide; D007930:Leucine; D010649:Phenylalanine; D020005:Propanols; D014443:Tyrosine; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated