The conformation and function of somatostatin (SST),
a cyclic neuropeptide,
was recently found to be altered in the presence of Cu(II) ions, which
leads to self-aggregation and loss of biological function as a neurotransmitter.
However, the impact of Cu(II) ions on the structure and function of
SST is not fully understood. In this work, transition metal ion Förster
resonance energy transfer (tmFRET) and native ion mobility-mass spectrometry
(IM-MS) were utilized to study the structures of well-defined gas-phase
ions of SST and of a smaller analogue, octreotide (OCT). The tmFRET
results suggest two binding sites of Cu(II) ions in both native-like
SST and OCT ions, either in close proximity to the disulfide bond
or complexed by two aromatic residues, consistent with results obtained
from collision-induced dissociation (CID). The former binding site
was reported to initiate aggregation of SST, while the latter binding
site could directly affect the essential motif for receptor binding
and therefore impair the biological function of SST and OCT when bound
to SST receptors. Our results demonstrate that tmFRET is capable of
locating transition metal ion binding sites in neuropeptides. Furthermore,
multiple distance constraints (tmFRET) and global shape (IM-MS) provide
additional structural insights of SST and OCT ions upon metal binding,
which is related to the self-aggregation mechanisms and overall biological
functions.
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