Diabetes Metab J.  2024 Jul;48(4):487-502. 10.4093/dmj.2023.0362.

Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease

• Zhang Y
• Wei S
• Jin EJ
• Jo Y
• Oh CM
• Bae GU
• Kang JS
• Ryu D

• KMID: 2558032
• DOI: http://doi.org/10.4093/dmj.2023.0362

Abstract

Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Keyword

Cardiovascular diseases; Metabolic diseases; Methylation; Protein-arginine N-methyltransferases

Figure

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  Fig. 1. Overview of mammalian protein arginine methyltransferases (PRMTs) domain. PRMTs constitute a family of nine annotated members, all of which share conserved catalytic domains with a high sequence similarity, featuring five well-conserved motifs, including motif I (VLD/EVGXGXG), motif post-I (V/IXG/AXD/E), motif II (F/I/VDI/L/K), motif post-II (double E loop), and motif III (LR/KXXG), in addition to a THW loop. From the perspectives of structural proteomics, motif I serves as the linchpin of the binding pocket for S-adenosyl-L-methionine (AdoMet) also known as S-adenosyl methionine (SAM), a methyl donor, within all PRMT isoforms, characterized by the presence of three highly conserved glycine residues. Motif post-I assumes responsibility for orchestrating hydrogen bonding interactions with the ribose hydroxyl moiety of AdoMet, facilitated by the participation of a glutamic or aspartic acid residue. Motif II contributes to the stabilization of motif I through the β-sheet formation, a structural reinforcement that ensures enzymatic fidelity. Motif post-II contains two glutamic acid residues, functioning for substrate arginine localization. Motif III collaboratively engages with motif II by forming a parallel β-sheet, further solidifying the structural integrity of PRMTs. Collectively, these motifs embody specific conserved sequences ensconced within PRMTs structural framework, with essential amino acid residues that enable them to intricately interact with arginine residues nestled within substrate proteins. The THW loop emerges as a structural signature featuring a triad of amino acid residues—threonine (T), histidine (H), and tryptophan (W). This structural motif assumes a pivotal role in substrate binding, concomitant with its contribution to the stabilization of the N-terminal α-helix. THW loop is strategically positioned proximate to the catalytic site of PRMT proteins, where it orchestrates specific enzymatic reactions with arginine residues within substrate proteins, culminating in the precise methylation modification. Distinct PRMTs also harbor specific characteristic motifs, such as Src homology 3 (SH3) domain and zinz finger, which are essential for their unique enzymatic functions. The PRMTs family facilitates methyl groups transfer from SAM to distinct arginine residues, exerting precise control over the stability, subcellular localization, and functional attributes of their target proteins.

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  Fig. 2. Types of protein arginine methyltransferases (PRMTs) and their histone targets. PRMTs are categorized into three types. Type I PRMTs, including PRMT1, 2, 3, 4, 6, and 8, generate monomethylarginine (MMA) as an intermediary before forming asymmetric dimethylarginine. PRMT5 and 9 are type II PRMTs which produce symmetric dimethylarginine. Type III PRMT, exemplified by PRMT7, exclusively produces MMA. PRMTs wields a profound impact on gene expression by methylating arginine on histones H2A, H2B, H3, and H4. H, histone; R, arginine.

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  Fig. 3. Aberrant protein arginine methyltransferases (PRMTs) expression-induced pathological alterations of cardiovascular and metabolic diseases. The dysregulation of PRMTs, either gain-of-function (overexpression) or loss-of-function (knockout or inhibition), gives rise to a wide array of characteristic pathological alterations in various tissues, ultimately contributing to the development of cardiovascular and metabolic diseases.

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