How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

Abstract

A reciprocal relationship between phosphorylation and O-glycosylation has been reported for many cellular processes and human diseases. The accumulated evidence points to the significant role these post-translational modifications play in aggregation and fibril formation. Simplified peptide model systems provide a means for investigating the molecular changes associated with protein aggregation. In this study, by using an amyloid-forming model peptide, we show that phosphorylation and glycosylation can affect folding and aggregation kinetics differently. Incorporation of phosphoserines, regardless of their quantity and position, turned out to be most efficient in preventing amyloid formation, whereas O-glycosylation has a more subtle effect. The introduction of a single beta-galactose does not change the folding behavior of the model peptide, but does alter the aggregation kinetics in a site-specific manner. The presence of multiple galactose residues has an effect similar to that of phosphorylation.

Phosphorylation as Conformational Switch from the Native to Amyloid State: Trp-Cage as a Protein Aggregation Model

“…4B, C). Bryan et al carried out FTIR measurements and simulations on collagen model peptides such as (Pro-Pro-Gly/Ala) 10 and assigned the component at 1629 cm -1 mainly to vibrations of the amide carbonyls located between two prolines in a triple helical conformation. 56 Although D9S(P) has a more diverse amino acid composition than the simple Pro-Pro-X model peptides, the 1629 cm -1 peak is clearly manifested.…”

“…To verify the feasibility of this hypothesis we have built a PPII triple helical polymer model for this peptide. The collagen triple helix X-ray structure of the [(Pro-ProGly) 10 salt-bridges arose between the collagen chains which might be a key event in oligomer stabilization (Fig. 5).…”

“…[9][10][11][12] There is increasing evidence that abnormal-or hyperphosphorylation might be the driving force in the intracellular aggregation of tau protein 13 , α-synuclein [14][15][16][17][18][19][20] and amyloid-β peptide. [21][22][23][24][25] The phosphorylation at specific Ser or Thr residues might promote the nucleation-dependent oligomerization and thus aggregation of these proteins by increasing the β-sheet character of the modified sequences.…”

Splitting of α‐Helical Structure as Molecular Basis for Abolishing an Amyloid Formation by Multiple Glycosylation: A Molecular Dynamics Simulation Study

“…12 They used a de novo designed peptide as a simplified amyloid model to decipher O-galactosylation effects. Natural galactosylation process was evidenced by structural analysis for the biological proteins.…”

“…However, the α-helical portion significantly decreased by multiple glycosylation on the Ser10 and Ser17, showing fine correlation with the experimental observation reported by Broncel and coworkers. 12 During the MD simulations, the central structure of the multiply glycosylated PP was divided into two separate regions accompanied by a steep drop in α-helical content. In this study, we suggest that the α-helical splitting is a key mechanism to explain the structural change induced by multiple glycosylation concerning to abolish the formation of amyloid in the model PP system.…”