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Nat Chem Biol. 2018 Feb 14;14(3):206-214. doi: 10.1038/nchembio.2576.

How many human proteoforms are there?

Author information

1
Department of Biology, ETH Zurich, Zürich, Switzerland.
2
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
3
Department of Chemistry, University of Georgia, Athens, Georgia, USA.
4
Department of Biomedical Sciences, Macquarie University, Sydney, New South Wales, Australia.
5
Department of Chemistry, Stanford University, Stanford, California, USA.
6
Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland, USA.
7
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
8
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
9
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, USA.
10
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, and Epigenetics Institute, Philadelphia, Pennsylvania, USA.
11
Department of Cell and Regenerative Biology, Human Proteomics Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
12
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
13
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
14
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
15
Department of Chemistry, University of Illinois, Urbana, Illinois, USA.
16
Department of Biosciences and Christian Doppler Laboratory for Biosimilar Characterization, University of Salzburg, Salzburg, Austria.
17
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
18
The Center for Synthetic Biology, Northwestern University, Evanston, Illinois, USA.
19
Department of Chemistry, Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
20
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
21
Department of Cellular Molecular Pharmacology, University of California, San Francisco, California, USA.
22
Department of Biological Chemistry, University of California, Los Angeles, California, USA.
23
Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
24
Department of Genetics, Stanford University, Stanford, California, USA.
25
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
26
Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
27
Department of Biology, Saint Mary's College of California, Moraga, California, USA.
28
Salk Institute for Biological Studies, Torrey Pines, California, USA.
29
Applied Proteomics, Genentech, Inc., San Francisco, California, USA.
30
Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg - Eppendorf, Hamburg, Germany.
31
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
32
Department of Chemistry, Yale University, New Haven, Connecticut, USA.
33
Genome Center of Wisconsin, Madison, Wisconsin, USA.
34
Department of Microbiology, KTH Royal Institute of Technology, Stockholm, Sweden.
35
Cedars Sinai Medical Center, Los Angeles, California, USA.
36
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
37
Department of Pathology, Harvard Medical School and Wyss Institute at Harvard University, Boston, Massachusetts, USA.
38
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
39
Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
40
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, USA.
41
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
42
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.

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.

PMID:
29443976
PMCID:
PMC5837046
[Available on 2019-02-14]
DOI:
10.1038/nchembio.2576

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