Format

Send to

Choose Destination
J Struct Biol. 2017 Aug;199(2):140-152. doi: 10.1016/j.jsb.2017.06.002. Epub 2017 Jun 14.

Tracking the amyloidogenic core of IAPP amyloid fibrils: Insights from micro-Raman spectroscopy.

Author information

1
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: nlouros@biol.uoa.gr.
2
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: etsiolaki@biol.uoa.gr.
3
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: fbaltoumas@biol.uoa.gr.
4
Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens 116 35, Greece. Electronic address: gdchryss@eie.gr.
5
Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens 116 35, Greece. Electronic address: vgionis@eie.gr.
6
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: shamodr@biol.uoa.gr.
7
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: veconom@biol.uoa.gr.

Abstract

Human islet amyloid polypeptide (hIAPP) is the major protein component of extracellular amyloid deposits, located in the islets of Langerhans, a hallmark of type II diabetes. The underlying mechanisms of IAPP aggregation have not yet been clearly defined, although the highly amyloidogenic sequence of the protein has been extensively studied. Several segments have been highlighted as aggregation-prone regions (APRs), with much attention focused on the central 8-17 and 20-29 stretches. In this work, we employ micro-Raman spectroscopy to identify specific regions that are contributing to or are excluded from the amyloidogenic core of IAPP amyloid fibrils. Our results demonstrate that both the N-terminal region containing a conserved disulfide bond between Cys residues at positions 2 and 7, and the C-terminal region containing the only Tyr residue are excluded from the amyloid core. Finally, by performing detailed aggregation assays and molecular dynamics simulations on a number of IAPP variants, we demonstrate that point mutations within the central APRs contribute to the reduction of the overall amyloidogenic potential of the protein but do not completely abolish the formation of IAPP amyloid fibrils.

KEYWORDS:

Aggregation-prone peptides; Amylin; Amyloidosis; Disulfide bonds; Raman Spectroscopy; Type II diabetes

PMID:
28602716
DOI:
10.1016/j.jsb.2017.06.002
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center