Synergy among Nuclear Receptor Coactivators: Selective Requirement for Protein Methyltransferase and Acetyltransferase Activities

Lee, Young Ho; Koh, Stephen S.; Zhang, Xing; Cheng, Xiaodong; Stallcup, Michael R.

doi:10.1128/mcb.22.11.3621-3632.2002

Cited by 160 publications

(196 citation statements)

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“…The importance of histone acetylation by p300͞CBP and p300͞CBP associated factor (p/CAF) and histone methylation by CARM1 and protein arginine methyltransferase 1 (PRMT1) has been clearly demonstrated (8,(11)(12)(13)(14)(15), although the mechanisms by which most of these histone modifications contribute to the transcriptional activation process still remain to be elucidated. However, in addition to histones, other proteins in the transcription machinery are modified posttranslationally.…”

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confidence: 99%

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Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination

Lee

Coonrod

Kraus

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear receptors activate transcription by recruiting multiple coactivators to the promoters of specific target genes. The functional synergy of the p160 coactivators [steroid receptor coactivator-1, glucocorticoid receptor interacting protein (GRIP1), or the activator for thyroid hormone and retinoid receptors], the histone acetyltransferases cAMP response element binding protein binding protein (CBP) and p300 and the histone methyltransferase coactivator-associated arginine methyltransferase (CARM1) depends on the methyltransferase activity of CARM1. CARM1 methylates histone H3 and other factors including the N-terminal region of p300. Here, we report that CARM1 also methylates Arg-2142 within the C-terminal GRIP1 binding domain (GBD) of p300. In the GBD, both Arg-2088 and Arg-2142 are important for binding GRIP1. Methylation of Arg-2142 inhibits the bimolecular interaction of GRIP1 to p300 in vitro and in vivo. This methylation mark of p300 GBD is removed by peptidyl deiminase 4, thereby enhancing the p300 -GRIP1 interaction. These methylation and demethylimination events also alter the conformation and activity of the coactivator complex and regulate estrogen receptor-mediated transcription, and they thus represent unique mechanisms for regulating coactivator complex assembly, conformation, and function.transcriptional regulation H ormone-activated nuclear receptors (NRs) activate transcription by binding to specific DNA regulatory elements in target gene promoters; there they recruit coactivator proteins to remodel chromatin structure and assemble the transcription complex containing RNA polymerase II (1, 2). The p160 coactivators [e.g., steroid receptor coactivator-1, glucocorticoid receptor interacting protein (GRIP1), and the activator for thyroid hormone and retinoid receptors] bind directly to hormone-activated NR and recruit secondary coactivators such as p300͞cAMP response element binding protein (CREB) binding protein (CBP) and coactivatorassociated arginine methyltransferase (CARM1), which acetylate and methylate (respectively) histones and other proteins in the transcription complex (3-5). These and other covalent modifications of histones and cofactors play important roles in chromatin remodeling and transcriptional regulation (6 -10).

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confidence: 99%

“…CARM1, p300͞CBP, and p160 coactivators function synergistically as NR coactivators (13). In addition to histone H3 (14,20), p300 and CBP are methylation substrates for CARM1.…”

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confidence: 99%

Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination

Lee

Coonrod

Kraus

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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205

183

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“…Two conformations are observed in all known crystal structures; a 'down' conformation as observed in CARM1 (Arg268) and PRMT3 (Ser336) and an 'up' conformation as observed in PRMT1 (Ser 154) and RMT1/Hmt1 (Ser142). It seems that there is a correlation between these two backbone conformations and the side chain orientation of Glu267, a conserved residue crucial for the catalytic mechanism (Zhang et al, 2000;Lee et al, 2002;Zhang and Cheng, 2003). In PRMT1 and RMT1/Hmt1 that display an 'up' conformation, the last glutamic acid residue of motif III points away from the catalytic center, whereas in CARM1 and PRMT3 it points towards it.…”

Section: Order-to-disorder Transition Upon Sah Binding On Carm1 140-480mentioning

confidence: 99%

“…The co-factor molecule is firmly locked and buried by three of the four aromatic rings of motif I. Tyr154 of motif I interacts with Glu267, a conserved residue that has been shown to be crucial for the protein methyltransferase activity (Lee et al, 2002). Therefore, as discussed below, structural changes of the N-terminal helices (aX, aY and aZ) are required during the catalytic pathway.…”

Section: S-adenosyl-l-homocysteine-binding Sitementioning

confidence: 99%

“…CARM1 transcriptional regulation is done by methylation of histone H3 (on Arg2, Arg17 and Arg26) and by protein-protein interactions with the p160 family of coactivators. As a transcriptional coactivator, CARM1 is a key player in the formation of large complexes on gene promoters leading to chromatin remodelling and gene activation (Lee et al, 2002;Xu et al, 2004;Feng et al, 2006;Naeem et al, 2007). It has been proposed that CARM1 may play a dual function first by activating transcription by modifying core histone tails and then by facilitating disassembly of the coactivator complex (Feng et al, 2006).…”

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Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains

Cavarelli¹,

Troffer-Charlier²,

Hassenboehler³

et al. 2008

Acta Cryst Sect A

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Coactivator-associated arginine methyltransferase 1 (CARM1), a protein arginine methyltransferase recruited by several transcription factors, methylates a large variety of proteins and plays a critical role in gene expression. We report, in this paper, four crystal structures of isolated modules of CARM1. The 1.7 Å crystal structure of the N-terminal domain of CARM1 reveals an unexpected PH domain, a scaffold frequently found to regulate protein-protein interactions in a large variety of biological processes. Three crystal structures of the CARM1 catalytic module, two free and one cofactor-bound forms (refined at 2.55 Å , 2.4 Å and 2.2 Å , respectively) reveal large structural modifications including disorder to order transition, helix to strand transition and active site modifications. The N-terminal and the C-terminal end of CARM1 catalytic module contain molecular switches that may inspire how CARM1 regulates its biological activities by protein-protein interactions.

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A Chloroacetamidine‐Based Inactivator of Protein Arginine Methyltransferase 1: Design, Synthesis, and In Vitro and In Vivo Evaluation

et al. 2010

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Protein arginine methyltransferases (PRMTs) catalyze the post-translational methylation of arginine residues. PRMT1 is the predominant mammalian isozyme, and is responsible for generating the majority of the asymmetrically dimethylated arginine found in vivo. The dysregulation of this enzyme has been implicated in heart disease and cancer; thus, its inhibition would be useful in the treatment of these diseases. Herein, we describe the most potent PRMT1 inhibitor described to date. This compound, denoted C21, is a chloroacetamidine-containing peptide that is able to irreversibly bind and inactivate the enzyme selectively. We have also shown that the coactivator activity of PRMT1 is selectively inhibited by the compound in cellulo. KeywordsProtein Arginine Methyltransferase; Citrulline; Cl-amidine; transcription; inactivator Over the last decade, arginine methylation has emerged as an important post-translational modification (PTM), and dysregulation of this process appears to contribute to the onset and/or progression of multiple human pathologies, including heart disease and cancer. [1][2][3] The Protein Arginine Methyltransferases (PRMTs) catalyze this modification, using Sadenosyl methionine as the methyl donor. To date, ≥10 putative and confirmed PRMT isozymes have been described in humans, and these enzymes have been shown to contribute to the regulation of numerous physiological processes, including RNA splicing, nuclearcytoplasmic shuttling, and transcriptional regulation. [1][2][3] Among the PRMTs, PRMT1 is arguably the best characterized enzyme at both the molecular and physiological levels. For example, its structure has been determined at atomic resolution,[4] and the enzyme has been shown to utilize a rapid equilibrium random mechanism, with the formation of dead-end EAP and EBQ complexes, to catalyze the formation of mono-and asymmetrically dimethylated arginine (ADMA) in a

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Synergy among Nuclear Receptor Coactivators: Selective Requirement for Protein Methyltransferase and Acetyltransferase Activities

Cited by 160 publications

References 42 publications

Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination

Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination

Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains

A Chloroacetamidine‐Based Inactivator of Protein Arginine Methyltransferase 1: Design, Synthesis, and In Vitro and In Vivo Evaluation

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