Estimating the Distribution of Protein Post-Translational Modification States by Mass Spectrometry

Philip D. Compton, Neil L. Kelleher*, Jeremy Gunawardena

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Post-translational modifications (PTMs) of proteins play a central role in cellular information encoding, but the complexity of PTM state has been challenging to unravel. A single molecule can exhibit a "modform" or combinatorial pattern of co-occurring PTMs across multiple sites, and a molecular population can exhibit a distribution of amounts of different modforms. How can this "modform distribution" be estimated by mass spectrometry (MS)? Bottom-up MS, based on cleavage into peptides, destroys correlations between PTMs on different peptides, but it is conceivable that multiple proteases with appropriate patterns of cleavage could reconstruct the modform distribution. We introduce a mathematical language for describing MS measurements and show, on the contrary, that no matter how many distinct proteases are available, the shortfall in information required for reconstruction worsens exponentially with increasing numbers of sites. Whereas top-down MS on intact proteins can do better, current technology cannot prevent the exponential worsening. However, our analysis also shows that all forms of MS yield linear equations for modform amounts. This permits different MS protocols to be integrated and the modform distribution to be constrained within a high-dimensional "modform region", which may offer a feasible proxy for analyzing information encoding.

Original languageEnglish (US)
Pages (from-to)2727-2734
Number of pages8
JournalJournal of Proteome Research
Volume17
Issue number8
DOIs
StatePublished - Aug 3 2018

Keywords

  • bottom-up MS
  • mass spectrometry
  • modform distribution
  • modform region
  • post-translational modification
  • proteoform
  • top-down MS

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Fingerprint Dive into the research topics of 'Estimating the Distribution of Protein Post-Translational Modification States by Mass Spectrometry'. Together they form a unique fingerprint.

Cite this