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

Troffer-Charlier, N.; Cura, Vincent; Hassenboehler, P.; Moras, Dino; Cavarelli, Jean

doi:10.1038/sj.emboj.7601855

Cited by 137 publications

(218 citation statements)

References 42 publications

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“…We suggest that this phenomenon may be a general principle that could be exploited for other PMTs. Indeed, the Post-SET element of SET-domain methyltransferases, and the a-X helix of PRMTs, both located at the SAM-binding site, are flexible and dynamic regions that adopt a catalytically competent conformation upon SAM binding 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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“…Hence, prediction of new PH‐like domains may identify residues that are functionally important for intracellular traffic. Since the initial discovery of classical PH domains, newly solved PH‐like structures have unexpectedly been found, both early on,17 and at least 10 times since 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. Each of these discoveries added a new family of PH‐like domains to a growing PH‐like clan 28.…”

Section: Introductionmentioning

confidence: 99%

Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains

Fidler¹,

Murphy²,

Courtis³

et al. 2016

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Advances in membrane cell biology are hampered by the relatively high proportion of proteins with no known function. Such proteins are largely or entirely devoid of structurally significant domain annotations. Structural bioinformaticians have developed profile‐profile tools such as HHsearch (online version called HHpred), which can detect remote homologies that are missed by tools used to annotate databases. Here we have applied HHsearch to study a single structural fold in a single model organism as proof of principle. In the entire clan of protein domains sharing the pleckstrin homology domain fold in yeast, systematic application of HHsearch accurately identified known PH‐like domains. It also predicted 16 new domains in 13 yeast proteins many of which are implicated in intracellular traffic. One of these was Vps13p, where we confirmed the functional importance of the predicted PH‐like domain. Even though such predictions require considerable work to be corroborated, they are useful first steps. HHsearch should be applied more widely, particularly across entire proteomes of model organisms, to significantly improve database annotations.

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“…The catalytic domain adopts the canonical arginine methyltransferase tertiary structure similar to the type I PRMTs, with an AdoMet binding domain containing the nucleotide binding Rossmann fold, followed by a β-sandwich domain involved in substrate binding. PRMT5 lacks the YFxxY motif seen in type I PRMTs (40), and this region, which is involved in binding both cofactor and substrate, adopts a very different conformation below the AdoMet binding site in PRMT5. In addition, the conserved THW motif of the type I PRMTs is FSW in human PRMT5.…”

Section: Catalytic Domain and Salient Features Of The Prmt5 Cofactor mentioning

confidence: 99%

Crystal structure of the human PRMT5:MEP50 complex

Antonysamy

Bonday

Campbell

et al. 2012

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

275

385

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Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically di-methylates the two-terminal ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed β-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition.epigenetics | protein-protein complex | A9145C P osttranslational methylation of lysine and arginine residues by protein lysine methyltransferases and protein arginine methyltransferases (PRMTs) alters the activity and interactions of substrate proteins, with crucial consequences to diverse cellular functions (1-3). Histone methylation is an epigenetic mark that plays a vital role in normal cell function, and whose dysregulation is associated with several diseases (4).The PRMT family of methyltransferases belongs to the largest class (class I) of S-adenosylmethionine (AdoMet)-dependent methyltransferase enzymes, responsible for the transfer of a methyl group from AdoMet to the arginine side-chains of histones and other proteins. PRMTs are further subdivided into type I, type II, type III, and type IV enzymes based on their patterns of arginine methylation. Eleven human PRMTs have been identified to date (5), and they all methylate the terminal guanidino nitrogen atoms of arginine residues. Type I PRMT enzymes (PRMT1, -2, -3, -4, -6, and -8) generate ω-NG-monomethyl and ω-NG,NG-asymmetric di-methyl arginines, whereas PRMT5 is a type II PRMT that catalyzes the formation of ω-NG-monomethyl and ω-NG,N′G-symmetric di-methyl arginine residues. PRMT7 was initially thought to have type II activity, but recent evidence suggests that it may be a type III enzyme that is only able to monomethylate substrates to form ω-NG-monomethyl arginine (6). A type IV enzyme that catalyses the formation of δ-N-methyl arginine has been identified in yeast (7). All PRMTs share the highly conserved methyltransferase catalytic domain, and several PRMTs contain additional domains that modulate their activity and specificity. PRMT2, PRMT3, and PRMT9 contain SH3, zinc finger, and TRP2 domains, respectively, and PRMT5 contains a largely uncharacterized N-terminal region.In contrast to type I PRMTs, PRMT5 functions as part of various high molecular weight protein complexes that invariably contain the WD-repe...

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

Cited by 137 publications

References 42 publications

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Using HHsearch to tackle proteins of unknown function: A pilot study with PH domains

Crystal structure of the human PRMT5:MEP50 complex

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