How many human proteoforms are there?,Nature Chemical Biology

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How many human proteoforms are there?
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2018-02-14 , DOI: 10.1038/nchembio.2576
Ruedi Aebersold ₁ , Jeffrey N Agar ₂ , I Jonathan Amster ₃ , Mark S Baker ₄ , Carolyn R Bertozzi ₅ , Emily S Boja ₆ , Catherine E Costello ₇ , Benjamin F Cravatt ₈ , Catherine Fenselau ₉ , Benjamin A Garcia ₁₀ , Ying Ge _{11,

12} , Jeremy Gunawardena ₁₃ , Ronald C Hendrickson ₁₄ , Paul J Hergenrother ₁₅ , Christian G Huber ₁₆ , Alexander R Ivanov ₂ , Ole N Jensen ₁₇ , Michael C Jewett ₁₈ , Neil L Kelleher ₁₉ , Laura L Kiessling ₂₀ , Nevan J Krogan ₂₁ , Martin R Larsen ₁₇ , Joseph A Loo ₂₂ , Rachel R Ogorzalek Loo ₂₂ , Emma Lundberg _{23,

24} , Michael J MacCoss ₂₅ , Parag Mallick ₅ , Vamsi K Mootha ₁₃ , Milan Mrksich ₁₈ , Tom W Muir ₂₆ , Steven M Patrie ₁₉ , James J Pesavento ₂₇ , Sharon J Pitteri ₅ , Henry Rodriguez ₆ , Alan Saghatelian ₂₈ , Wendy Sandoval ₂₉ , Hartmut Schlüter ₃₀ , Salvatore Sechi ₃₁ , Sarah A Slavoff ₃₂ , Lloyd M Smith _{12,

33} , Michael P Snyder ₂₄ , Paul M Thomas ₁₉ , Mathias Uhlén ₃₄ , Jennifer E Van Eyk ₃₅ , Marc Vidal ₃₆ , David R Walt ₃₇ , Forest M White ₃₈ , Evan R Williams ₃₉ , Therese Wohlschlager ₁₆ , Vicki H Wysocki ₄₀ , Nathan A Yates ₄₁ , Nicolas L Young ₄₂ , Bing Zhang ₄₂

Affiliation

Department of Biology, ETH Zurich, Zürich, Switzerland.
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
Department of Chemistry, University of Georgia, Athens, Georgia, USA.
Department of Biomedical Sciences, Macquarie University, Sydney, New South Wales, Australia.
Department of Chemistry, Stanford University, Stanford, California, USA.
Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, USA.
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, and Epigenetics Institute, Philadelphia, Pennsylvania, USA.
Department of Cell and Regenerative Biology, Human Proteomics Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Chemistry, University of Illinois, Urbana, Illinois, USA.
Department of Biosciences and Christian Doppler Laboratory for Biosimilar Characterization, University of Salzburg, Salzburg, Austria.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
The Center for Synthetic Biology, Northwestern University, Evanston, Illinois, USA.
Department of Chemistry, Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Department of Cellular Molecular Pharmacology, University of California, San Francisco, California, USA.
Department of Biological Chemistry, University of California, Los Angeles, California, USA.
Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
Department of Genetics, Stanford University, Stanford, California, USA.
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
Department of Biology, Saint Mary's College of California, Moraga, California, USA.
Salk Institute for Biological Studies, Torrey Pines, California, USA.
Applied Proteomics, Genentech, Inc., San Francisco, California, USA.
Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg - Eppendorf, Hamburg, Germany.
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
Department of Chemistry, Yale University, New Haven, Connecticut, USA.
Genome Center of Wisconsin, Madison, Wisconsin, USA.
Department of Microbiology, KTH Royal Institute of Technology, Stockholm, Sweden.
Cedars Sinai Medical Center, Los Angeles, California, USA.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pathology, Harvard Medical School and Wyss Institute at Harvard University, Boston, Massachusetts, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, USA.
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.

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.

中文翻译：

人类有多少种蛋白质？

尽管几十年来积累了有关蛋白质及其翻译后修饰 (PTM) 的知识，但有关其分子组成和生物功能的许多问题仍然存在。最基本的问题之一是 DNA、RNA 和 PTM 水平变异的组合在多大程度上会导致人类蛋白质组的复杂性爆炸。在这里，我们概述了我们从当前数据库和测量策略（包括基于质谱的蛋白质组学）中了解到的信息。在此过程中，我们研究了关于人类蛋白质上显示的修饰数量以及它们如何结合以产生健康和疾病背后的蛋白质多样性的流行观念。我们提出了有关确定蛋白质水平变异和 PTM 的核心问题，包括当今该领域存在的一些悖论。我们使用这个框架来评估现有数据并提出以下问题：“20,300 个人类基因创建了多少种不同的蛋白质一级结构（蛋白质形式）？” 我们还探索了改进测量的前景，以更好地规范蛋白质水平生物学并有效地将 PTM 与功能和表型相关联。

更新日期：2018-02-14

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