Modification of histidine repeat proteins by inorganic polyphosphate
Nolan Neville,
Kirsten Lehotsky,
Zhiyun Yang,
Kody A. Klupt,
Alix Denoncourt,
Michael Downey,
Zongchao Jia
Affiliations
Nolan Neville
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
Kirsten Lehotsky
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
Zhiyun Yang
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
Kody A. Klupt
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
Alix Denoncourt
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada
Michael Downey
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada
Zongchao Jia
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; Corresponding author
Summary: Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate that is present in nearly all organisms studied to date. A remarkable function of polyP involves its attachment to lysine residues via non-enzymatic post-translational modification (PTM), which is presumed to be covalent. Here, we show that proteins containing tracts of consecutive histidine residues exhibit a similar modification by polyP, which confers an electrophoretic mobility shift on NuPAGE gels. Our screen uncovers 30 human and yeast histidine repeat proteins that undergo histidine polyphosphate modification (HPM). This polyP modification is histidine dependent and non-covalent in nature, although remarkably it withstands harsh denaturing conditions—a hallmark of covalent PTMs. Importantly, we show that HPM disrupts phase separation and the phosphorylation activity of the human protein kinase DYRK1A, and inhibits the activity of the transcription factor MafB, highlighting HPM as a potential protein regulatory mechanism.
