The Novel Protease Activities of JMJD5-JMJD6-JMJD7 and Arginine Methylation Activities of Arginine Methyltransferases Are Likely Coupled

Abstract

The surreptitious discoveries of the protease activities on arginine-methylated targets of a subfamily of Jumonji domain-containing family including JMJD5, JMJD6, and JMJD7 pose several questions regarding their authenticity, function, purpose, and relations with others. At the same time, despite several decades of efforts and massive accumulating data regarding the roles of the arginine methyltransferase family (PRMTs), the exact function of this protein family still remains a mystery, though it seems to play critical roles in transcription regulation, including activation and inactivation of a large group of genes, as well as other biological activities. In this review, we aim to elucidate that the function of JMJD5/6/7 and PRMTs are likely coupled. Besides roles in the regulation of the biogenesis of membrane-less organelles in cells, they are major players in regulating stimulating transcription factors to control the activities of RNA Polymerase II in higher eukaryotes, especially in the animal kingdom. Furthermore, we propose that arginine methylation by PRMTs could be a ubiquitous action marked for destruction after missions by a subfamily of the Jumonji protein family.

Keywords: JMJD5; JMJD6; JMJD7; Jumonji; PRMT.

Figure 1

Possible histone methylation. Histone lysine methylation is very specific and limited while histone arginine methylation seems not specific and ubiquitous.

Figure 2

Methylation promotes the interaction between positively charged sidechains (cations) and aromatic cage ($\mathsf{\pi }$). Kme3, trimethylation of Lysine; Rme2s, symmetric di-methylation of arginine. (A). Detailed interactions between PHD domain and tri-methylated lysine. (B). Detailed interactions between Tudor domain and symmetrically di-methylated arginine. (C). Detailed interactions between the substrate-binding domain of JMJD5 and symmetrically di-methylated arginine.

Figure 3

A model of transcription activation and arginine methylation on +1 nucleosome. A transcription unit includes enhancers, transcription factors (TFs), p300/CBP, nuclear receptor co-activator (NCoA), arginine methyltransferase 1 or 4 (PRMT1, CARM1), arginine methylated histone tails at +1 nucleosome. H3.3K27ac, acetylated H3.3 subunit; H4Kac, acetylated H4 subunit; H3.3K4me1, monomethylated H3.3K4; H2/3/4Rme2a/s, arginine methylated histone subunits H2, H3, and H4. GT, general transcription factors. The following figures have the same labels.

Figure 4

A model of how MLL3/4 is recruited by arginine methylated histones on +1 nucleosome. MLL3/4 complex is recruited by arginine methylated histone tails at +1 nucleosome through PHD domains and/or WDR domain-containing proteins, is responsible for generating H3.3K4me1 at enhancers. MLL3/4, Myeloid/Lymphoid or Mixed-Lineage Leukemia Protein 3/4. WDR, WD repeating-containing protein.

Figure 5

A model of transcription of how KDM3/4 is recruited by arginine methylated histone on +1 nucleosome. KDM3/4 are H3K9 and H3K36 specific lysine demethylases to remove methyl groups on H3.3K9 at enhancer regions. Tudor domain is specific to recognize arginine methylated histone tails at +1 nucleosome.

Figure 6

A model of transcription repression and arginine methylation on +1 nucleosome. When transcription repressors (TF2) bind to the enhancer regions, which recruit nuclear receptor co-repressor (NCoR). NCoR, in turn, recruits PRMT5/6 to generate methylated arginine on the +1 nucleosome.

Figure 7

A model of how SETDB1 is recruited by arginine methylated histone on +1 nucleosome. SETDB1 will be recruited through the Tudor domain within SETDB1 and methylates H3.3K9 to generate H3.3K9me3. H3.3K9me3, trimethylated H3.3K9.

Figure 8

A model of how heterochromatin is formed by HP1 after methylation of H3K9. H3.3K9me3 will recruit HP1protein to form heterochromatin. HP1, heterochromatin protein 1.

Figure 9

The endopeptidase and carboxy-exopeptidase activities of c-JMJD5 and c-JMJD7 on synthesized histone tails. (A). c-JMJD5 and mutant c-JMJD5 cleavage on H3R2me2s. The top portion is the sequence of the H3R2me2s peptide with symmetric di-methylation on R2 with MW 2749.47 Da. After cleavage, a major band of MW 2494.3 (peak A) is the product of peptide with the first two residues missing. (B). c-JMJD7 generated a similar profile [23].

Figure 10

The structural basis of specific recognition between methylated arginine and JMJD5. (A). Detailed interactions between demethylated arginine and JMJD5. (B). A diagram shows the potential catalysis mechanism and specific recognition between methylated arginine and JMJD5 [24].

Figure 11

The endopeptidase and amino-exopeptidase activities of JMJD6 on MePCE. (A). Mass data from Orbitrap Velos, (B). Mass assignments, (C). Peptide AA Seq.