How many human proteoforms are there?

Ruedi Aebersold, Jeffrey N. Agar, I. Jonathan Amster, Mark S. Baker, Carolyn R. Bertozzi, Emily S. Boja, Catherine E. Costello, Benjamin F. Cravatt, Catherine Fenselau, Benjamin A. Garcia, Ying Ge, Jeremy Gunawardena, Ronald C. Hendrickson, Paul J. Hergenrother, Christian G. Huber, Alexander R. Ivanov, Ole N. Jensen, Michael C. Jewett, Neil L. Kelleher, Laura L. KiesslingNevan J. Krogan, Martin R. Larsen, Joseph A. Loo, Rachel R. Ogorzalek Loo, Emma Lundberg, Michael J. Maccoss, Parag Mallick, Vamsi K. Mootha, Milan Mrksich, Tom W. Muir, Steven M. Patrie, James J. Pesavento, Sharon J. Pitteri, Henry Rodriguez, Alan Saghatelian, Wendy Sandoval, Hartmut Schlüter, Salvatore Sechi, Sarah A. Slavoff, Lloyd M. Smith, Michael P. Snyder, Paul M. Thomas, Mathias Uhlén, Jennifer E. Van Eyk, Marc Vidal, David R. Walt, Forest M. White, Evan R. Williams, Therese Wohlschlager, Vicki H. Wysocki, Nathan A. Yates, Nicolas L. Young, Bing Zhang

Research output: Contribution to journalReview article

133 Scopus citations

Abstract

Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA- and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.

Original languageEnglish (US)
Pages (from-to)206-214
Number of pages9
JournalNature Chemical Biology
Volume14
Issue number3
DOIs
StatePublished - Feb 14 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Aebersold, R., Agar, J. N., Amster, I. J., Baker, M. S., Bertozzi, C. R., Boja, E. S., Costello, C. E., Cravatt, B. F., Fenselau, C., Garcia, B. A., Ge, Y., Gunawardena, J., Hendrickson, R. C., Hergenrother, P. J., Huber, C. G., Ivanov, A. R., Jensen, O. N., Jewett, M. C., Kelleher, N. L., ... Zhang, B. (2018). How many human proteoforms are there? Nature Chemical Biology, 14(3), 206-214. https://doi.org/10.1038/nchembio.2576