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Metabolic Mapping: Quantitative Enzyme Cytochemistry and Histochemistry to Determine the Activity of Dehydrogenases in Cells and Tissues
Published on: May 26, 2018
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Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition
Evgenia Shishkova1, Hao Zeng2, Fabao Liu2
1The Department of Biomolecular Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.
Nature Communications
|May 25, 2017
Summary
Coactivator-associated arginine methyltransferase 1 (CARM1) methylates proteins, impacting health and disease. Researchers identified over 130 CARM1 substrates, revealing its N-terminus is crucial for methylation and a potential target for cancer therapies.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a critical post-translational modification.
- Coactivator-associated arginine methyltransferase 1 (CARM1) is implicated in cancer, but its substrates and recognition mechanisms are largely unknown.
- Understanding CARM1 function is vital for developing targeted cancer therapies.
Purpose of the Study:
- To globally identify protein substrates of CARM1 using quantitative mass spectrometry.
- To elucidate the mechanism of substrate recognition by CARM1.
- To explore the therapeutic potential of targeting CARM1 in cancer.
Main Methods:
- Quantitative mass spectrometry was employed to profile CARM1 substrates in breast cancer cell lines.
- In vitro validation was performed to confirm identified methylation sites.
- Bioinformatics analyses were conducted to identify sequence motifs and mutation patterns.
Main Results:
- >130 CARM1 protein substrates were identified, with over 90% of sites validated in vitro.
- Proline-containing motifs were enriched among substrates, and these regions are frequently mutated in cancer.
- The N-terminus of CARM1 was found to be essential for substrate recognition and methylation.
Conclusions:
- CARM1 plays a significant role in arginine methylation, with implications for cancer pathogenesis.
- The N-terminus of CARM1 is a key determinant of substrate recognition and a promising target for inhibitor development.
- Similar substrate recognition mechanisms may be employed by other PRMTs.
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