A single mutation on the human amyloid polypeptide modulates fibril growth and affects the mechanism of amyloid-induced membrane damage

Anais R F Hoffmann; Manikam Sadasivam Saravanan; Olivier Lequin; J Antoinette Killian; Lucie Khemtemourian

doi:10.1016/j.bbamem.2018.02.018

A single mutation on the human amyloid polypeptide modulates fibril growth and affects the mechanism of amyloid-induced membrane damage

Biochim Biophys Acta Biomembr. 2018 Sep;1860(9):1783-1792. doi: 10.1016/j.bbamem.2018.02.018. Epub 2018 Feb 27.

Authors

Anais R F Hoffmann¹, Manikam Sadasivam Saravanan², Olivier Lequin¹, J Antoinette Killian², Lucie Khemtemourian³

Affiliations

¹ Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, 4 place Jussieu, F-75005 Paris, France.
² Department of Chemistry, Faculty of Science, Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Padualaan 8, 3584 Utrecht, The Netherlands.
³ Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, 4 place Jussieu, F-75005 Paris, France. Electronic address: lucie.khemtemourian@upmc.fr.

PMID: 29499190
DOI: 10.1016/j.bbamem.2018.02.018

Abstract

Amyloid fibril formation has been implicated in a wide range of human diseases and the interactions of amyloidogenic proteins with cell membranes are considered to be important in the aetiology of these pathologies. In type 2 diabetes mellitus (T2DM), the human islet amyloid polypeptide (hIAPP) forms amyloid fibrils which impair the functionality and viability of pancreatic β cells. The mechanisms of hIAPP cytotoxicity are linked to the ability of the peptide to self-aggregate and to interact with membranes. Previous studies have shown that the N-terminal part of hIAPP from residues 1 to 19 is the membrane binding domain. The non-amyloidogenic and nontoxic mouse IAPP differs from hIAPP by six residues out of 37, among which a single one, residue 18, lies in the membrane binding region. To gain more insight into hIAPP-membrane interactions we herein performed comprehensive biophysical studies on four analogues (H18R-IAPP, H18K-IAPP, H18E-IAPP and H18A-IAPP). Our data reveal that all peptides are able to insert efficiently in the membrane, indicating that residue 18 is not essential for hIAPP membrane binding and insertion. However, only wild-type hIAPP and H18K-IAPP are able to form fibrils at the membrane. Importantly, all peptides induce membrane damage; wild-type hIAPP and H18K-IAPP presumably cause membrane disruption mainly by fibril growth at the membrane, while for H18R-IAPP, H18E-IAPP and H18A-IAPP, membrane leakage is most likely due to high molecular weight oligomeric species. These results highlight the importance of the residue at position 18 in IAPP for modulating fibril formation at the membrane and the mechanisms of membrane leakage.

Keywords: Aggregation kinetics; Amyloid-membrane interactions; Islet amyloid polypeptide; Membrane leakage; Model membranes (LUV); Type 2 diabetes mellitus.