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Structural studies of protein arginine methyltransferase 2 reveal its interactions with potential substrates and inhibitors
Author(s) -
Cura Vincent,
Marechal Nils,
TrofferCharlier Nathalie,
Strub JeanMarc,
Haren Matthijs J.,
Martin Nathaniel I.,
Cianférani Sarah,
Bonnefond Luc,
Cavarelli Jean
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13953
Subject(s) - methylation , biology , microbiology and biotechnology , biochemistry , gene
PRMT 2 is the less‐characterized member of the protein arginine methyltransferase family in terms of structure, activity, and cellular functions. PRMT 2 is a modular protein containing a catalytic Ado‐Met‐binding domain and unique Src homology 3 domain that binds proteins with proline‐rich motifs. PRMT 2 is involved in a variety of cellular processes and has diverse roles in transcriptional regulation through different mechanisms depending on its binding partners. PRMT 2 has been demonstrated to have weak methyltransferase activity on a histone H4 substrate, but its optimal substrates have not yet been identified. To obtain insights into the function and activity of PRMT 2, we solve several crystal structures of PRMT 2 from two homologs (zebrafish and mouse) in complex with either the methylation product S‐adenosyl‐L‐homocysteine or other compounds including the first synthetic PRMT 2 inhibitor (Cp1) studied so far. We reveal that the N‐terminal‐containing SH 3 module is disordered in the full‐length crystal structures, and highlights idiosyncratic features of the PRMT 2 active site. We identify a new nonhistone protein substrate belonging to the serine‐/arginine‐rich protein family which interacts with PRMT 2 and we characterize six methylation sites by mass spectrometry. To better understand structural basis for Cp1 binding, we also solve the structure of the complex PRMT 4:Cp1. We compare the inhibitor–protein interactions occurring in the PRMT 2 and PRMT 4 complex crystal structures and show that this compound inhibits efficiently PRMT 2. These results are a first step toward a better understanding of PRMT 2 substrate recognition and may accelerate the development of structure‐based drug design of PRMT 2 inhibitors. Database All coordinates and structure factors have been deposited in the Protein Data Bank: zPRMT2 1‐408 ‐SFG = 5g02 ; zPRMT2 73‐408 ‐SAH = 5fub ; mPRMT2 1‐445 ‐SAH = 5ful ; mPRMT2 1‐445 ‐Cp1 = 5fwa , mCARM1 130‐487 ‐Cp1 = 5k8v .