title: Insights into the consequences of co-polymerisation in the early stages of IAPP and Aβ peptide assembly from mass spectrometry.
abstract: The precise molecular mechanisms by which different peptides and proteins assemble into highly ordered amyloid deposits remain elusive. The fibrillation of human amylin (also known as islet amyloid polypeptide, hIAPP) and the amyloid-beta peptide (Aβ-40) are thought to be pathogenic factors in Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Amyloid diseases may involve co-aggregation of different protein species, in addition to the self-assembly of single precursor sequences. Here we investigate the formation of heterogeneous pre-fibrillar, oligomeric species produced by the co-incubation of hIAPP and Aβ-40 using electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS)-based methods. Conformational properties and gas-phase stabilities of amyloid oligomers formed from hIAPP or Aβ40 alone, and from a 1 : 1 mixture of hIAPP and Aβ40 monomers, were determined and compared. We show that co-assembly of the two sequences results in hetero-oligomers with distinct properties and aggregation kinetics properties compared with the homo-oligomers present in solution. The observations may be of key significance to unravelling the mechanisms of amyloid formation in vivo and elucidating how different sequences and/or assembly conditions can result in different fibril structures and/or pathogenic outcomes.
authors.affiliation: Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, LS2 9JT, UK. s.e.radford@leeds.ac.uk a.e.ashcroft@leeds.ac.uk.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Young
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Mahood
authors.forename: Janet C
authors.initials: JC
authors.lastname: Saunders
authors.forename: Ling-Hsien
authors.initials: LH
authors.lastname: Tu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
authors.forename: Alison E
authors.initials: AE
authors.lastname: Ashcroft
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)