Islet amyloid polypeptide inserts into phospholipid monolayers as monomer

Engel, M.F.M., Yigittop, H., Elgersma, R.C., Rijkers, D.T.S., Liskamp, R.M.J. , de Kruijff, B., Höppener, J.W.M. and Antoinette Killian, J. (2006) Islet amyloid polypeptide inserts into phospholipid monolayers as monomer. Journal of Molecular Biology, 356(3), pp. 783-789. (doi: 10.1016/j.jmb.2005.12.020)

Abstract

Amyloid deposits in the pancreatic islets of Langerhans are thought to be a main factor responsible for death of the insulin-producing islet β-cells in type 2 diabetes. It is hypothesized that β-cell death is related to interaction of the 37 amino acid residue human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid, with cellular membranes. However, the mechanism of hIAPP–membrane interactions is largely unknown. Here, we study the nature and the molecular details of the initial step of hIAPP–membrane interactions by using the monolayer technique. It is shown that both freshly dissolved hIAPP and the non-amyloidogenic mouse IAPP (mIAPP) have a pronounced ability to insert into phospholipid monolayers, even at lipid packing conditions that exceed the conditions that occur in biological membranes. In contrast, the fibrillar form of hIAPP has lost the ability to insert. These results, combined with the observations that both the insertion kinetics and the dependence of insertion on the initial surface pressure are similar for freshly dissolved hIAPP and mIAPP, indicate that hIAPP inserts into phospholipid monolayers most likely as a monomer. In addition, our results suggest that the N-terminal part of hIAPP, which is nearly identical with that of mIAPP, is largely responsible for insertion. This is supported by experiments with hIAPP fragments, which show that a peptide consisting of the 19 N-terminal residues of hIAPP efficiently inserts into phospholipid monolayers, whereas an amyloidogenic decapeptide, consisting of residues 20–29 of hIAPP, inserts much less efficiently. The results obtained here suggest that hIAPP monomers might insert with high efficiency in biological membranes in vivo. This process could play an important role as a first step in hIAPP-induced membrane damage in type 2 diabetes.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liskamp, Professor Robert
• Authors: Engel, M.F.M., Yigittop, H., Elgersma, R.C., Rijkers, D.T.S., Liskamp, R.M.J., de Kruijff, B., Höppener, J.W.M., and Antoinette Killian, J.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Molecular Biology
• ISSN: 0022-2836
• ISSN (Online): 1089-8638