How many human proteoforms are there? Author Ruedi Aebersold, Jeffrey Agar, I Jonathan Amster, Mark Baker, Carolyn Bertozzi, Emily Boja, Catherine Costello, Benjamin Cravatt, Catherine Fenselau, Benjamin Garcia, Ying Ge, Jeremy Gunawardena, Ronald Hendrickson, Paul Hergenrother, Christian Huber, Alexander Ivanov, Ole Jensen, Michael Jewett, Neil Kelleher, Laura Kiessling, Nevan Krogan, Martin Larsen, Joseph Loo, Rachel Loo, Emma Lundberg, Michael MacCoss, Parag Mallick, Vamsi Mootha, Milan Mrksich, Tom Muir, Steven Patrie, James Pesavento, Sharon Pitteri, Henry Rodriguez, Alan Saghatelian, Wendy Sandoval, Hartmut Schlüter, Salvatore Sechi, Sarah Slavoff, Lloyd Smith, Michael Snyder, Paul Thomas, Mathias Uhlén, Jennifer Van Eyk, Marc Vidal, David Walt, Forest White, Evan Williams, Therese Wohlschlager, Vicki Wysocki, Nathan Yates, Nicolas Young, Bing Zhang Publication Year 2018 Type Journal Article 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. Keywords Protein Biosynthesis, Humans, Mass Spectrometry, Phenotype, Protein Processing, Post-Translational, Proteomics, Proteome, Databases, Protein, Proteins, Genome, Human, Ubiquitin, Protein Isoforms Journal Nat Chem Biol Volume 14 Issue 3 Pages 206-214 Date Published 2018 Feb 14 ISSN Number 1552-4469 DOI 10.1038/nchembio.2576 Alternate Journal Nat Chem Biol PMCID PMC5837046 PMID 29443976 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML