Top-down identification and characterization of biomolecules by mass spectrometry

  • Kathrin Breuker
  • Mi Jin
  • Xuemei Han
  • Honghai Jiang
  • Fred W. McLafferty
Focus: Desorption Ionization And Macromolecular MS

Abstract

The most widely used modern mass spectrometers face severe performance limitations with molecules larger than a few kDa. For far larger biomolecules, a common practice has been to break these up chemically or enzymatically into fragments that are sufficiently small for the instrumentation available. With its many sophisticated recent enhancements, this “bottom-up” approach has proved highly valuable, such as for the rapid, routine identification and quantitation of DNA-predicted proteins in complex mixtures. Characterization of smaller molecules, however, has always measured the mass of the molecule and then that of its fragments. This “top-down” approach has been made possible for direct analysis of large biomolecules by the uniquely high (>105) mass resolving power and accuracy (∼1 ppm) of the Fourier-transform mass spectrometer. For complex mixtures, isolation of a single component’s molecular ions for MS/MS not only gives biomolecule identifications of far higher reliability, but directly characterizes sequence errors and post-translational modifications. Protein sizes amenable for current MS/MS instrumentation are increased by a “middle-down” approach in which limited proteolysis forms large (e.g., 10 kDa) polypeptides that are then subjected to the top-down approach, or by “prefolding dissociation.” The latter, which extends characterization to proteins >200 kDa, was made possible by greater understanding of how molecular ion tertiary structure evolves in the gas phase.

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Copyright information

© American Society for Mass Spectrometry 2008

Authors and Affiliations

  • Kathrin Breuker
    • 1
  • Mi Jin
    • 2
  • Xuemei Han
    • 2
  • Honghai Jiang
    • 2
  • Fred W. McLafferty
    • 2
  1. 1.Institute of Organic Chemistry and Center for Molecular Biosciences InnsbruckUniversity of InnsbruckInnsbruckAustria
  2. 2.Department of Chemistry and Chemical BiologyCornell UniversityIthacaUSA

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