We investigate the physicochemical effects of pyroglutamination
on the QHALTSV-NH2 peptide, a segment of cytosolic helix
8 of the human C–X–C chemokine G-protein-coupled receptor
type 4 (CXCR4). This modification, resulting from the spontaneous
conversion of glutamine to pyroglutamic acid, has significant impacts
on the physicochemical features of peptides. Using a static approach,
we compared the transformation in different conditions and experimentally
found that the rate of product formation increases with temperature,
underscoring the need for caution during laboratory experiments to
prevent glutamine cyclization. Circular dichroism experiments revealed
that the QHALTSV-NH2 segment plays a minor role in the
structuration of H8 CXCR4; however, its pyroglutaminated analogue
interacts differently with its chemical environment, showing increased
susceptibility to solvent variations compared to the native form.
The pyroglutaminated analogue exhibits altered behavior when interacting
with lipid models, suggesting a significant impact on its interaction
with cell membranes. A unique combination of atomic force microscopy
and infrared nanospectroscopy revealed that pyroglutamination affects
supramolecular self-assembly, leading to highly packed molecular arrangements
and a crystalline structure. Moreover, the presence of pyroglumatic
acid has been found to favor the formation of amyloidogenic aggregates.
Our findings emphasize the importance of considering pyroglutamination
in peptide synthesis and proteomics and its potential significance
in amyloidosis.
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