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A Genetic Toggle for Chemical Control of Individual Plk1 Substrates.
Johnson, James M; Hebert, Alexander S; Drane, Quentin H; Lera, Robert F; Wan, Jun; Weaver, Beth A; Coon, Joshua J; Burkard, Mark E.
Affiliation
  • Johnson JM; Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, 1111 Highland Avenue, WIMR 6059, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA.
  • Hebert AS; Genome Center, University of Wisconsin, Madison, WI 53705, USA; Morgridge Institute for Research, Madison, WI 53705, USA.
  • Drane QH; Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, 1111 Highland Avenue, WIMR 6059, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA.
  • Lera RF; Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, 1111 Highland Avenue, WIMR 6059, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA.
  • Wan J; Physiology Training Program, University of Wisconsin, Madison, WI 53705, USA.
  • Weaver BA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA; Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705, USA; Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53705, USA
  • Coon JJ; Genome Center, University of Wisconsin, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53705, USA; Morgridge Institute for Research, Madison, WI 53705, USA.
  • Burkard ME; Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, 1111 Highland Avenue, WIMR 6059, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA; Department of Oncology/McArdle Laboratory for Cancer Research, Un
Cell Chem Biol ; 27(3): 350-362.e8, 2020 03 19.
Article in En | MEDLINE | ID: mdl-32017920
ABSTRACT
Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphoproteomic analysis of mitotic cell extracts showed that Plk1S (L197F) and Plk1T (L197S/L211A) selectively phosphorylate Ser and Thr, respectively. Plk1S but not Plk1T sustains mitotic progression to anaphase, affording the opportunity to toggle substrate residues between Ser and Thr to place them under chemical control. Using this system, we evaluated Kif2b, a known substrate of Plk1 that regulates chromosome alignment. Toggling Ser to Thr on Kif2b places these phosphorylation sites under reversible chemical control, as indicated by a sharp increase in the frequency of misaligned chromosomes and prometaphase arrest. Thus, we demonstrate the ability to chemically control a single substrate by a genetic Ser/Thr toggle.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine / Threonine / Proto-Oncogene Proteins / Protein Serine-Threonine Kinases / Cell Cycle Proteins Limits: Humans Language: En Journal: Cell Chem Biol Year: 2020 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine / Threonine / Proto-Oncogene Proteins / Protein Serine-Threonine Kinases / Cell Cycle Proteins Limits: Humans Language: En Journal: Cell Chem Biol Year: 2020 Document type: Article Affiliation country: United States