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Publication Abstract from PubMed

Type-I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of various proteins, and their dysregulations often correlate with tumorigenesis or developmental deficiency. Recent studies have focused on the in vivo substrate identification and the enzyme mechanism with peptide substrates. However, how PRMTs recognize substrates at the protein level remain unknown. PRMT8 is one of the least characterized type-I PRMTs and its crystal structure has not been reported. Here, we report the crystal structure of PRMT8:SAH complex, identify a new non-histone protein substrate NIFK, and uncover a previously unknown regulatory region specifically required for recognizing NIFK. Instead of the canonical dimeric structure for other type-I PRMTs, PRMT8 exists as tetramer in solution. Using X-ray crystallography in combination with small angle X-ray scattering experiments, the dimer of dimers architecture where two PRMT8 dimers are held together mainly by beta-strand interactions was proposed. Mutation of PRMT8-beta15 impedes the methylation of NIFK but still allows methylation of histone H2A/H2B dimer or a peptide substrate, suggesting a possible structural basis for recognition of protein substrates. Lastly, we observed two PRMT8 dimer orientations resulting in open (without SAH) and closed (with SAH bound) conformations. The comparison be-tween open and closed conformations may provide useful information for PRMT1/8 inhibitor design.

PROTEIN ARGININE METHYLTRANSFERASE 8: tetrameric structure and protein substrate specificity.,Lee WC, Lin WL, Matsui T, Chen ES, Wei TW, Lin WH, Hu H, Zheng YG, Tsai MD, Ho MC Biochemistry. 2015 Nov 3. PMID:26529540^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.