Human pro-islet amyloid polypeptide (ProIAPP(1-48)) forms amyloid fibrils and amyloid spherulites in vitro.
Deposition of beta sheets of islet amyloid polypeptide (IAPP) in pancreatic tissue is implicated in the aetiology of type 2 diabetes mellitus (T2DM). IAPP is cleaved from its precursor protein, pro-islet amyloid polypeptide (ProIAPP) and incomplete cleavage results in ProIAPP(1-48), which is found co-deposited with IAPP. Cu(II) prevents IAPP from forming amyloid and herein we investigated if it would also prevent ProIAPP(1-48) from forming beta sheets. Excess Cu(II) prevented ProIAPP(1-48) from forming amyloid and additionally reversed the formation of beta sheets in pre-formed fibrils of the peptide. The latter was also true for ProIAPP(1-48) fibrils formed in the presence of Al(III). An unexpected finding was the formation of spherulites of ProIAPP(1-48) which were only observed in preparations which included Al(III). The spherulites were 40-100 microm in diameter and stained positively for Al(III) suggesting a role for this metal in their formation. The abolition by Cu(II) of the propensity of ProIAPP(1-48) to form amyloid may have important implications for the treatment of T2DM. The immediate significance for diabetes of the equally novel observation of spherulites of ProIAPP(1-48) is unknown though, as with spherulites of Abeta(42) in Alzheimer's disease, there may be implications for the aetiology of the disease.
Exley
Christopher
C
The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK. c.exley@chem.keele.ac.uk
House
Emily
E
Patel
Trisha
T
Wu
Ling
L
Fraser
Paul E
PE
D000535:Aluminum / Q000737:chemistry*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D003300:Copper / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008859:Microscopy, Polarization; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C422904:pro-islet amyloid polypeptide; D003300:Copper; D000535:Aluminum