Pinpointing phosphorylation sites: Quantitative filtering and a novel site-specific x-ion fragment

J Proteome Res. 2011 Jul 1;10(7):2937-48. doi: 10.1021/pr200154t. Epub 2011 Apr 28.

Abstract

Phosphoproteomics deals with the identification and quantification of thousands of phosphopeptides. Localizing the phosphorylation site is however much more difficult than establishing the identity of a phosphorylated peptide. Further, recent findings have raised doubts of the validity of the site assignments in large-scale phosphoproteomics data sets. To improve methods for site localization, we made use of a synthetic phosphopeptide library and SILAC-labeled peptides from whole cell lysates and analyzed these with high-resolution tandem mass spectrometry on an LTQ Orbitrap Velos. We validated gas-phase phosphate rearrangement reactions during collision-induced dissociation (CID) and used these spectra to devise a quantitative filter that by comparing signal intensities of putative phosphorylated fragment ions with their nonphosphorylated counterparts allowed us to accurately pinpoint which fragment ions contain a phosphorylated residue and which ones do not. We also evaluated higher-energy collisional dissociation (HCD) and found this to be an accurate method for correct phosphorylation site localization with no gas-phase rearrangements observed above noise level. Analyzing a large set of HCD spectra of SILAC-labeled phosphopeptides, we identified a novel fragmentation mechanism that generates a phosphorylation site-specific neutral loss derived x-ion, which directly pinpoints the phosphorylated residue. Together, these findings significantly improve phosphorylation site localization confidence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Cell Extracts / analysis*
  • Cell Extracts / chemistry
  • Energy Transfer
  • Gases / chemistry
  • HEK293 Cells
  • Humans
  • Ions / chemistry
  • Molecular Sequence Data
  • Peptide Fragments / analysis*
  • Peptide Fragments / chemistry
  • Phosphates / chemistry
  • Phosphopeptides / analysis
  • Phosphopeptides / chemistry
  • Phosphorylation
  • Proteomics / methods*
  • Software
  • Tandem Mass Spectrometry / methods*
  • Trypsin / metabolism

Substances

  • Cell Extracts
  • Gases
  • Ions
  • Peptide Fragments
  • Phosphates
  • Phosphopeptides
  • Trypsin