Interaction of membrane-bound islet amyloid polypeptide with soluble and crystalline insulin

Protein Sci. 2008 Oct;17(10):1850-6. doi: 10.1110/ps.036350.108. Epub 2008 Sep 2.

Abstract

Islet amyloid polypeptide (IAPP, also known as amylin) is the major protein component of pancreatic amyloid fibers in type II diabetes and is normally cosecreted with insulin from the beta-cells of the pancreas. IAPP forms amyloid fibrils rapidly at concentrations well below those found in vivo, yet progression of type II diabetes occurs over many years. Insulin, a known inhibitor of IAPP fibrillogenesis, exists as a dense crystalline or near-crystalline core in the secretory vesicle, while IAPP localizes to the region between the crystal and the secretory vesicle membrane. In vitro, IAPP fibrillogenesis is both accelerated by lipid membranes and inhibited by monomeric insulin. In this work, we investigate insulin-IAPP-lipid interactions in vitro under conditions chosen to approximate native secretory vesicle physiology and the amyloid disease state. The effect of insulin on IAPP fibrillogenesis is investigated using fluorescence spectrometry. Additionally, interactions of IAPP and lipids with crystalline insulin are studied using fluorescence microscopy. We find that, while soluble states of insulin and IAPP do not interact significantly, large assemblies of either insulin (crystals) or IAPP (fibers) can lead to stable IAPP-insulin interactions. The results raise the possibility of multiple physiological interactions between these two beta-cell hormones.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Animals
  • Crystallization
  • Humans
  • Insulin / chemistry*
  • Insulin-Secreting Cells
  • Islet Amyloid Polypeptide
  • Lipid Bilayers / chemistry*
  • Liposomes / chemistry
  • Molecular Sequence Data
  • Protein Binding
  • Rats
  • Spectrometry, Fluorescence

Substances

  • Amyloid
  • Insulin
  • Islet Amyloid Polypeptide
  • Lipid Bilayers
  • Liposomes