Panoramic Perspective on Human Phosphosites

Protein
phosphorylation is the most common reversible post-translational
modification of proteins and is key in the regulation of many cellular
processes. Due to this importance, phosphorylation is extensively
studied, resulting in the availability of a large amount of mass spectrometry-based
phospho-proteomics data. Here, we leverage the information in these
large-scale phospho-proteomics data sets, as contained in Scop3P,
to analyze and characterize proteome-wide protein phosphorylation
sites (P-sites). First, we set out to differentiate correctly observed
P-sites from false-positive sites using five complementary site properties.
We then describe the context of these P-sites in terms of the protein
structure, solvent accessibility, structural transitions and disorder,
and biophysical properties. We also investigate the relative prevalence
of disease-linked mutations on and around P-sites. Moreover, we assess
the structural dynamics of P-sites in their phosphorylated and unphosphorylated
states. As a result, we show how large-scale reprocessing of available
proteomics experiments can enable a more reliable view on proteome-wide
P-sites. Furthermore, adding the structural context of proteins around
P-sites helps uncover possible conformational switches upon phosphorylation.
Moreover, by placing sites in different biophysical contexts, we show
the differential preference in protein dynamics at phosphorylated
sites when compared to the nonphosphorylated counterparts.