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Global profiling of phosphorylation-dependent changes in cysteine reactivity
Esther K Kemper1, Yuanjin Zhang2, Melissa M Dix2
1The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. ekemper@scripps.edu.
Nature Methods
|March 1, 2022
Summary
This study introduces a chemical proteomics method to link serine/threonine phosphorylation to cysteine reactivity. This reveals how phosphorylation impacts protein structure and function, aiding in the development of targeted therapies.
Area of Science:
- Biochemistry
- Proteomics
- Chemical Biology
Background:
- Proteomics reveals a vast diversity of human proteoforms generated by post-translational modifications (PTMs).
- Assessing the impact of PTMs on protein structure and function across the proteome remains a significant technical challenge.
Purpose of the Study:
- To develop a chemical proteomic method for quantitatively linking serine/threonine phosphorylation to cysteine reactivity.
- To investigate how phosphorylation influences the chemical properties of cysteine residues, impacting their modification potential and interaction with covalent drugs.
Main Methods:
- A novel chemical proteomic approach was employed to measure changes in cysteine reactivity.
- The method leveraged high-stoichiometry phosphorylation in mitotic cells to identify affected cysteines.
- Quantitative analysis related phosphorylation events to alterations in cysteine reactivity.
Main Results:
- Numerous cysteines exhibiting phosphorylation-dependent reactivity changes were identified on diverse proteins.
- Proteins involved in cell cycle regulation were particularly enriched for these modifications.
- Bidirectional changes in cysteine reactivity were frequently observed near serine/threonine phosphorylation sites.
Conclusions:
- Phosphorylation has a broad influence on the chemical reactivity of proteins.
- This work provides a foundation for developing small-molecule probes that can selectively target proteoforms based on their PTM status.
- Understanding phosphorylation-dependent reactivity changes opens new avenues for drug discovery and therapeutic development.
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