Mammalian Protein Arginine Methyltransferase 7 (PRMT7) Specifically Targets RXR Sites in Lysine- and Arginine-rich Regions

Feng, You; Maity, Ranjan; Whitelegge, Julian P.; Hadjikyriacou, Andrea; Li, Ziwei; Zurita-Lopez, Cecilia; Al-Hadid, Qais; Clark, Amander T.; Bedford, Mark T.; Masson, Jean‐Yves; Clarke, Steven

doi:10.1074/jbc.m113.525345

Cited by 149 publications

(223 citation statements)

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“…High resolution cation exchange chromatography was then performed as described previously (8). The positions of the amino acid standards were determined using 570-nm absorbance after ninhydrin assay with 50 l of column fractions (8). Radioactivity in 950 l of each fraction was determined with liquid scintillation as described (8) but using the average of three 3-min counting cycles.…”

Section: Methodsmentioning

confidence: 99%

“…After removal of the HCl by vacuum centrifugation, samples were dissolved in 50 l of water and mixed with 1 mol each of -MMA (acetate salt; Sigma, M7033), SDMA (di-(p-hydroxyazobenzene)-pЈ-sulfonate salt; Sigma, D0390), and ADMA (hydrochloride salt; Sigma, D4268) as internal standards. High resolution cation exchange chromatography was then performed as described previously (8). The positions of the amino acid standards were determined using 570-nm absorbance after ninhydrin assay with 50 l of column fractions (8).…”

Section: Methodsmentioning

confidence: 99%

“…However, PRMT7 has been found to produce MMA residues only, which defines it as the first type III PRMT (5)(6)(7)(8)(9). Recent work utilizing an insect cell-expressed mouse PRMT7 demonstrated a unique substrate specificity for RXR motifs among multiple basic residues (8). No other PRMT has been shown to have such narrow sequence specificity.…”

mentioning

confidence: 99%

“…Most mammalian PRMTs have been characterized as either type I enzymes that transfer up to two methyl groups from S-adenosyl-L-methionine (AdoMet) to the same terminal nitrogen atom forming -N G -monomethylarginine (MMA) and -N G ,N G -asymmetric dimethylarginine (ADMA) (PRMT1, -2, -3, -4, -6, and -8) or type II enzymes that transfer up to two methyl groups to different terminal nitrogen atoms, forming MMA and -N G ,NЈ Gsymmetric dimethylarginine (SDMA) (PRMT5) (1)(2)(3)(4). However, PRMT7 has been found to produce MMA residues only, which defines it as the first type III PRMT (5)(6)(7)(8)(9). Recent work utilizing an insect cell-expressed mouse PRMT7 demonstrated a unique substrate specificity for RXR motifs among multiple basic residues (8).…”

mentioning

confidence: 99%

“…Although the insect cell-expressed mouse PRMT7 showed higher catalytic activity than the bacterially expressed GST-tagged human PRMT7 (7,8), site-directed mutagenesis and protein expression and purification are facilitated in the bacterial system. In this work, we used the bacterial system to determine which residues of human PRMT7 are important for substrate recognition.…”

mentioning

confidence: 99%

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Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Feng¹,

Hadjikyriacou²,

Clarke³

2014

Journal of Biological Chemistry

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107

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Background: Mammalian PRMT7 has been implicated in multiple biological processes, but its in vivo substrates have not been identified. Results: Mutagenesis studies indicate key residues that affect the unique substrate preference of PRMT7. Conclusion: Acidic residues within the double E loop confer specificity to PRMT7. Significance: Understanding how PRMT7 recognizes its substrates will enhance our knowledge of its physiological role.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Feng¹,

Hadjikyriacou²,

Clarke³

2014

Journal of Biological Chemistry

Self Cite

107

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Promiscuous Enzymes for Residue‐Specific Peptide and Protein Late‐Stage Functionalization

Alexander

Elshahawi

2023

ChemBioChem

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The late‐stage functionalization of peptides and proteins holds significant promise for drug discovery and facilitates bioorthogonal chemistry. This selective functionalization leads to innovative advances in in vitro and in vivo biological research. However, it is a challenging endeavor to selectively target a certain amino acid or position in the presence of other residues containing reactive groups. Biocatalysis has emerged as a powerful tool for selective, efficient, and economical modifications of molecules. Enzymes that have the ability to modify multiple complex substrates or selectively install nonnative handles have wide applications. Herein, we highlight enzymes with broad substrate tolerance that have been demonstrated to modify a specific amino acid residue in simple or complex peptides and/or proteins at late‐stage. The different substrates accepted by these enzymes are mentioned together with the reported downstream bioorthogonal reactions that have benefited from the enzymatic selective modifications.

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Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease

Clemons

Acosta

Udo

et al. 2022

Journal Cellular Physiology

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Alzheimer's disease (AD) is the leading cause of mortality, disability, and long‐term care burden in the United States, with women comprising the majority of AD diagnoses. While AD‐related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO‐mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO−∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type‐1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT‐qPCR and protein analyses suggest that aged (9−12 months) female mice bearing tau‐ and amyloid beta‐producing transgenic mutations (3xTg‐AD) express higher levels of PRMT4 in the hippocampus when compared to age‐ and sex‐matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg‐AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free‐radical ONOO−, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's‐related cerebrovascular derangement.

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Mammalian Protein Arginine Methyltransferase 7 (PRMT7) Specifically Targets RXR Sites in Lysine- and Arginine-rich Regions

Cited by 149 publications

References 56 publications

Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Promiscuous Enzymes for Residue‐Specific Peptide and Protein Late‐Stage Functionalization

Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease

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