Characterization of Amyloid Formation by Glucagon-Like
Peptides: Role of Basic Residues in Heparin-Mediated Aggregation
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Abstract
Glycosaminoglycans (GAGs) have been
reported to play a significant role in amyloid formation of a wide
range of proteins/peptides either associated with diseases or native
biological functions. The exact mechanism by which GAGs influence
amyloid formation is not clearly understood. Here, we studied two
closely related peptides, glucagon-like peptide 1 (GLP1) and glucagon-like
peptide 2 (GLP2), for their amyloid formation in the presence and
absence of the representative GAG heparin using various biophysical
and computational approaches. We show that the aggregation and amyloid
formation by these peptides follow distinct mechanisms: GLP1 follows
nucleation-dependent aggregation, whereas GLP2 forms amyloids without
any significant lag time. Investigating the role of heparin, we also
found that heparin interacts with GLP1, accelerates its aggregation,
and gets incorporated within its amyloid fibrils. In contrast, heparin
neither affects the aggregation kinetics of GLP2 nor gets embedded
within its fibrils. Furthermore, we found that heparin preferentially
influences the stability of the GLP1 fibrils over GLP2 fibrils. To
understand the specific nature of the interaction of heparin with
GLP1 and GLP2, we performed all-atom MD simulations. Our in silico
results show that the basic-nonbasic-basic (B-X-B) motif of GLP1 (K28-G29-R30)
facilitates the interaction between heparin and peptide monomers.
However, the absence of such a motif in GLP2 could be the reason for
a significantly lower strength of interaction between GLP2 and heparin.
Our study not only helps to understand the role of heparin in inducing
protein aggregation but also provides insight into the nature of heparin–protein
interaction