Phosphorylation Sites with S/T-P Motif: Possible Basal Anti-Aggregation Mechanism

Abstract

Protein phosphorylation is the most common post-translational modification (PTM) found in eukaryotic proteome. One of the common sequence motifs found in phosphorylation sites is serine/threonine phosphorylation sites followed by proline residue ((S/T)-P). While this motif is found in up to 1/3 of whole human phosphorylation sites, individual sites with this motif are less well characterized, leaving most of its functions unknown.When compared to other serine/threonine phosphorylation sites, phosphorylation sites with (S/T)-P motif could be distinguished by distinct sequence profiles and biophysical properties. One of the notable features of (S/T)-P motif is its strong association with intrinsically disordered regions (IDR): not only most phosphorylation sites with (S/T)-P motif are found in long unfolded/non-globular regions, the frequency of (S/T)-P motif is positively correlated with fraction of IDR within proteome. On the other hand, relatively small number of corresponding kinases and higher sequence diversity imply that phosphorylation of (S/T)-P motif is rather promiscuous. Phenotype studies also show that missense mutation of (S/T)-P motif has lower frequency of being pathogenic than mutation of other phosphorylation sites.Based on all these findings, we hypothesized that phosphorylation of (S/T)-P motif plays an undiscovered fundamental role in the cellular environment via a simple biophysical mechanism, specifically IDR aggregation avoidance. Phosphorylation of (S/T)-P motif promotes the formation of alpha-helix and polyproline II (PII) conformations locally, thereby preventing accumulation of beta-strands and lower the possibility of adopting amyloid-like structures. This hypothesis may provide explanation to two questions: how this motif is associated with IDR, and why this motif is enriched in the eukaryotic proteome.