title: β-Hairpin of Islet Amyloid Polypeptide Bound to an Aggregation Inhibitor.
abstract: In type 2 diabetes, the formation of islet amyloid consisting of islet amyloid polypeptide (IAPP) is associated with reduction in β-cell mass and contributes to the failure of islet cell transplantation. Rational design of inhibitors of IAPP amyloid formation has therapeutic potential, but is hampered by the lack of structural information on inhibitor complexes of the conformationally flexible, aggregation-prone IAPP. Here we characterize a β-hairpin conformation of IAPP in complex with the engineered binding protein β-wrapin HI18. The β-strands correspond to two amyloidogenic motifs, 12-LANFLVH-18 and 22-NFGAILS-28, which are connected by a turn established around Ser-20. Besides backbone hydrogen bonding, the IAPP:HI18 interaction surface is dominated by non-polar contacts involving hydrophobic side chains of the IAPP β-strands. Apart from monomers, HI18 binds oligomers and fibrils and inhibits IAPP aggregation and toxicity at low substoichiometric concentrations. The IAPP β-hairpin can serve as a molecular recognition motif enabling control of IAPP aggregation.
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Mirecka
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Feuerstein
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.|Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.|Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Schröder
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.|Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stoldt
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.|Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.|Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425 Jülich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoyer
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D066329:Protein Aggregates / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012694:Serine / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D012694:Serine