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Advancing Top-down Analysis of the Human Proteome Using a Benchtop Quadrupole-Orbitrap Mass Spectrometer

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Departments of Chemistry and Molecular Biosciences, Northwestern University, 2170 Campus Drive, Evanston, Illinois 60208, United States
*E-mail: [email protected]. Phone: 847-467-4362. Fax: 847-467-3276.
Cite this: J. Proteome Res. 2017, 16, 2, 609–618
Publication Date (Web):November 16, 2016
Copyright © 2016 American Chemical Society

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    Over the past decade, developments in high resolution mass spectrometry have enabled the high throughput analysis of intact proteins from complex proteomes, leading to the identification of thousands of proteoforms. Several previous reports on top-down proteomics (TDP) relied on hybrid ion trap–Fourier transform mass spectrometers combined with data-dependent acquisition strategies. To further reduce TDP to practice, we use a quadrupole-Orbitrap instrument coupled with software for proteoform-dependent data acquisition to identify and characterize nearly 2000 proteoforms at a 1% false discovery rate from human fibroblasts. By combining a 3 m/z isolation window with short transients to improve specificity and signal-to-noise for proteoforms >30 kDa, we demonstrate improving proteome coverage by capturing 439 proteoforms in the 30–60 kDa range. Three different data acquisition strategies were compared and resulted in the identification of many proteoforms not observed in replicate data-dependent experiments. Notably, the data set is reported with updated metrics and tools including a new viewer and assignment of permanent proteoform record identifiers for inclusion of highly characterized proteoforms (i.e., those with C-scores >40) in a repository curated by the Consortium for Top-Down Proteomics.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jproteome.6b00698.

    • Analytical SDS-PAGE gels run to visualize fractions from a GELFrEE separation of whole cell extracts of human IMR90 fibroblasts; mass accuracy of the “medium”-resolution approach to MS1 as a function of protein molecular weight; example of identifying a low-abundance proteoform via SIM marching; graphical output of STRING Gene Ontology analysis based on accession numbers of larger proteins identified by experiments run with “medium/high” data acquisition logic; distribution of all 1952 proteoforms identified at a 1% proteoform-level FDR; correlation between q-values and C-scores for the proteoforms identified by AUTOPILOT high/high experiments at 1% proteoform-level FDR (PDF)

    • List of identifications including entries and proteoforms for data-dependent high/high experiments (XLSX)

    • List of identifications including entries and proteoforms for AUTOPILOT high/high experiments (XLSX)

    • List of identifications including entries and proteoforms for data-dependent medium/high experiments (XLSX)

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