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Nat Commun. 2017 May 24;8:15571. doi: 10.1038/ncomms15571.

Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition.

Author information

1
The Department of Biomolecular Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.
2
McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.
3
The Genome Center of Wisconsin, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.
4
The Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53705, USA.

Abstract

Protein arginine methyltransferases (PRMTs) introduce arginine methylation, a post-translational modification with the increasingly eminent role in normal physiology and disease. PRMT4 or coactivator-associated arginine methyltransferase 1 (CARM1) is a propitious target for cancer therapy; however, few CARM1 substrates are known, and its mechanism of substrate recognition is poorly understood. Here we employed a quantitative mass spectrometry approach to globally profile CARM1 substrates in breast cancer cell lines. We identified >130 CARM1 protein substrates and validated in vitro >90% of sites they encompass. Bioinformatics analyses reveal enrichment of proline-containing motifs, in which both methylation sites and their proximal sequences are frequently targeted by somatic mutations in cancer. Finally, we demonstrate that the N-terminus of CARM1 is involved in substrate recognition and nearly indispensable for substrate methylation. We propose that development of CARM1-specific inhibitors should focus on its N-terminus and predict that other PRMTs may employ similar mechanism for substrate recognition.

PMID:
28537268
PMCID:
PMC5458078
DOI:
10.1038/ncomms15571
[Indexed for MEDLINE]
Free PMC Article

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