In:
Peptide Science, Wiley, Vol. 104, No. 3 ( 2015-05), p. 196-205
Abstract:
Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic β‐cells leading to type II diabetes mellitus. Human mature islet amyloid polypeptide (hIAPP), a 37‐residue pancreatic hormone, has been identified as the primary component of amyloid fibrils forming these deposits. Several individual segments along the entire sequence length of hIAPP have been nominated as regions with increased amyloidogenic potential, such as regions 8–20, 20–29, and 30–37. A smaller fragment of the 8–20 region, spanning residues 8–16 of hIAPP has been associated with the formation of early transient α‐helical dimers that promote fibrillogenesis and also as a core part of hIAPP amyloid fibrils. Utilizing our aggregation propensity prediction tools AmylPred and AmylPred2, we have identified the high aggregation propensity of the 8–16 segment of hIAPP. A peptide analog corresponding to this segment was chemically synthesized and its amyloidogenic properties were validated using electron microscopy, X‐ray fiber diffraction, ATR FT‐IR spectroscopy, and polarized microscopy. Additionally, two peptides introducing point mutations L12R and L12P, respectively, to the 8–16 segment, were chemically synthesized. Both mutations disrupt the α‐helical properties of the 8–16 region and lower its amyloidogenic potential, which was confirmed experimentally. Finally, cytotoxicity assays indicate that the 8–16 segment of hIAPP shows enhanced cytotoxicity, which is relieved by the L12R mutation but not by the L12P mutation. Our results indicate that the chameleon properties and the high aggregation propensity of the 8–16 region may significantly contribute to the formation of amyloid fibrils and the overall cytotoxic effect of hIAPP. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 196–205, 2015.
Type of Medium:
Online Resource
ISSN:
0006-3525
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2159538-0
detail.hit.zdb_id:
1480801-8
SSG:
12
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