title: Functional insights from high resolution structures of mouse protein arginine methyltransferase 6.
abstract: PRMT6 is a protein arginine methyltransferase involved in transcriptional regulation, human immunodeficiency virus pathogenesis, DNA base excision repair, and cell cycle progression. Like other PRMTs, PRMT6 is overexpressed in several cancer types and is therefore considered as a potential anti-cancer drug target. In the present study, we described six crystal structures of PRMT6 from Mus musculus, solved and refined at 1.34 Å for the highest resolution structure. The crystal structures revealed that the folding of the helix αX is required to stabilize a productive active site before methylation of the bound peptide can occur. In the absence of cofactor, metal cations can be found in the catalytic pocket at the expected position of the guanidinium moiety of the target arginine substrate. Using mass spectrometry under native conditions, we show that PRMT6 dimer binds two cofactor and a single H4 peptide molecules. Finally, we characterized a new site of in vitro automethylation of mouse PRMT6 at position 7.
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bonnefond
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC-DSA, Université de Strasbourg, CNRS, UMR7178, 25 rue Becquerel, Strasbourg 67087, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Stojko
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Mailliot
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Troffer-Charlier
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cura
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Wurtz
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC-DSA, Université de Strasbourg, CNRS, UMR7178, 25 rue Becquerel, Strasbourg 67087, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cianférani
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR7104, INSERM U964, 1 rue Laurent Fries, Illkirch, F-67404, France. Electronic address: cava@igbmc.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D013058:Mass Spectrometry; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry* / Q000502:physiology; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C577312:PRMT6 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
keywords: Epigenetics; Methyltransferase; PRMT6; Protein structure; S-adenosyl-l-methionine