title: Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets.
abstract: Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register β sheets, which may constitute one of the toxic species in aggregation related diseases. Here we sought to determine the presence of such a motif in islet amyloid polypeptide (IAPP), whose amyloidogenic properties are associated with type 2 diabetes. We determined four new crystal structures of segments within IAPP, all forming steric zippers. Most interestingly, one of the segments in the fibril core of IAPP forms an out-of-register steric zipper. Analysis of this structure reveals several commonalities with previously solved out-of-register fibrils. Our results provide additional evidence of out-of-register β sheets as a common structural motif in amyloid aggregates.
authors.affiliation: Howard Hughes Medical Institute, ‡UCLA-DOE Institute of Genomics and Proteomics, §Department of Biological Chemistry, and ∥Department of Chemistry & Biochemistry, UCLA , Los Angeles, California 90095, United States.
authors.forename: Angela B
authors.initials: AB
authors.lastname: Soriaga
authors.affiliation: Howard Hughes Medical Institute, ‡UCLA-DOE Institute of Genomics and Proteomics, §Department of Biological Chemistry, and ∥Department of Chemistry & Biochemistry, UCLA , Los Angeles, California 90095, United States.
authors.forename: Smriti
authors.initials: S
authors.lastname: Sangwan
authors.affiliation: Howard Hughes Medical Institute, ‡UCLA-DOE Institute of Genomics and Proteomics, §Department of Biological Chemistry, and ∥Department of Chemistry & Biochemistry, UCLA , Los Angeles, California 90095, United States.
authors.forename: Ramsay
authors.initials: R
authors.lastname: Macdonald
authors.affiliation: Howard Hughes Medical Institute, ‡UCLA-DOE Institute of Genomics and Proteomics, §Department of Biological Chemistry, and ∥Department of Chemistry & Biochemistry, UCLA , Los Angeles, California 90095, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: Howard Hughes Medical Institute, ‡UCLA-DOE Institute of Genomics and Proteomics, §Department of Biological Chemistry, and ∥Department of Chemistry & Biochemistry, UCLA , Los Angeles, California 90095, United States.
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D066329:Protein Aggregates; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D012996:Solutions; D013816:Thermodynamics
chemical_list: D058228:Islet Amyloid Polypeptide; D010455:Peptides; D066329:Protein Aggregates; D012996:Solutions