Katrine Kirkeby Skeby, Ole Juul Andersen, Taras V. Pogorelov, Emad Tajkhorshid,
and Birgit Schiott.
Conformational dynamics of the human islet amyloid polypeptide in a
membrane environment: Toward the aggregation prone form.
Biochemistry, 55:2031-2042, 2016.
SKEB2016-ET
Human islet amyloid polypeptide (hIAPP) is a 37-residue
peptide hormone, which upon misfolding changes from the physiologically
active monomer into pathological amyloid fibril aggregates in the pancreas
of
type 2 diabetes mellitus patients. During this process, the insulin-
producing
pancreatic -cells are damaged; however, the underlying mechanism
of
this
mode of cytotoxicity remains elusive. It is known that anionic lipids
accelerate amyloid fibril formation, implicating the importance of the
cellular
membrane in the process, and that a pH close to the level in the -
cell
secretory granules (pH 5.5) inhibits amyloid fibril formation. Using all-atom
molecular dynamics simulations, we have investigated the
membraneassociated
monomer state of -helical hIAPP, analyzed specific interactions of
hIAPP
with a mixed anionic-zwitterionic lipid
membrane and examined the influence of pH on the structure and
dynamics of
hIAPP and its interaction with the membrane.
We find that hIAPP primarily interacts with the membrane by forming
favorable
interactions between anionic lipids and the
positively charged residues in the N-terminal part of the peptide.
Rationalizing
experimental findings, the simulations show that
the N-terminal part of the peptide interacts with the membrane in the lipid
headgroup region. At neutral pH, the C-terminal part
of the peptide, which contains the residues that initiate fibril formation,
displays a highly dynamic, unfolded state, which interacts
with the membrane significantly less than the N-terminal part. Such an
unfolded form can be proposed to contribute to the
acceleration of fibril formation. At low pH, protonation of His18 mediates a
stronger interaction of the C-terminal part with the
membrane, resulting in the immobilization of the C-terminal part on the
membrane surface that might constitute a mechanism
by which low pH inhibits fibril formation.
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