Post-translational methylation at arginine residues is one of the most important covalent modifications of proteins, involved in a myriad of essential cellular processes in eukaryotes, such as transcriptional regulati...Post-translational methylation at arginine residues is one of the most important covalent modifications of proteins, involved in a myriad of essential cellular processes in eukaryotes, such as transcriptional regulation, RNA processing, signal transduction, and DNA repair. Methylation at arginine residues is catalyzed by a family of enzymes called protein arginine methyltransferases （PRMTs）. PRMTs have been extensively studied in various taxa and there is a growing tendency to unveil their functional importance in plants. Recent studies in plants revealed that this evolutionarily conserved family of enzymes regulates essential traits including vegetative growth, flowering time, circadian cycle, and response to high medium salinity and ABA. In this review, we highlight recent advances in the field of post- translational arginine methylation with special emphasis on the roles and future prospects of this modification in plants.展开更多
Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a ...Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.展开更多
Arabidopsis AtPRMT10 is a plant-specific type I protein arginine methyltransferase that can asymmetrically dimethylate arginine 3 of histone H4 with auto-methylation activity.Mutations of AtPRMT10 derepress FLOWERING ...Arabidopsis AtPRMT10 is a plant-specific type I protein arginine methyltransferase that can asymmetrically dimethylate arginine 3 of histone H4 with auto-methylation activity.Mutations of AtPRMT10 derepress FLOWERING LOCUS C(FLC)expression resulting in a late-flowering phenotype.Here,to further investigate the biochemical characteristics of AtPRMT10,we analyzed a series of mutated forms of the AtPRMT10 protein.We demon-strate that the conserved“VLD”residues and“double-E loop”are essential for enzymatic activity of AtPRMT10.In addition,we show that Arg54 and Cys259 of AtPRMT10,two residues unreported in animals,are also important for its enzymatic activity.We find that Arg13 of AtPRMT10 is the auto-methylation site.However,substitution of Arg13 to Lys13 does not affect its enzymatic activity.In vivo complementation assays reveal that plants expressing AtPRMT10 with VLD-AAA,E143Q or E152Q mutations retain high levels of FLC expression and fail to rescue the late-flowering phenotype of atprmt10 plants.Taken together,we conclude that the methyltransferase activity of AtPRMT10 is essential for repressing FLC expression and promoting flowering in Arabidopsis.展开更多
基金supported by National Basic Research Program of China(grant Nos.2011CB9154002009CB941500)+1 种基金National Natural Science Foundation of China(grant No.30621001)the Chinese Academy of Sciences(Grant No.KSCX2-YW-N-047) to X.Cao
文摘Post-translational methylation at arginine residues is one of the most important covalent modifications of proteins, involved in a myriad of essential cellular processes in eukaryotes, such as transcriptional regulation, RNA processing, signal transduction, and DNA repair. Methylation at arginine residues is catalyzed by a family of enzymes called protein arginine methyltransferases （PRMTs）. PRMTs have been extensively studied in various taxa and there is a growing tendency to unveil their functional importance in plants. Recent studies in plants revealed that this evolutionarily conserved family of enzymes regulates essential traits including vegetative growth, flowering time, circadian cycle, and response to high medium salinity and ABA. In this review, we highlight recent advances in the field of post- translational arginine methylation with special emphasis on the roles and future prospects of this modification in plants.
基金support from NIH P30 CA023168(Purdue University Center for Cancer Research)the NSERC grant(RGPIN-2021-02728(Jinrong Min)).
文摘Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.
基金supported by the National Basic Research Program of China(Nos.2011CB915400 and 2009CB941500 to X.C.)the National Natural Science Foundation of China(Grant Nos.30930048 and 30921061 to X.C.,and 90919033 to C.L.)the Chinese Academy of Sciences(No.KSCX2-EW-Q-24-02 to C.L.)。
文摘Arabidopsis AtPRMT10 is a plant-specific type I protein arginine methyltransferase that can asymmetrically dimethylate arginine 3 of histone H4 with auto-methylation activity.Mutations of AtPRMT10 derepress FLOWERING LOCUS C(FLC)expression resulting in a late-flowering phenotype.Here,to further investigate the biochemical characteristics of AtPRMT10,we analyzed a series of mutated forms of the AtPRMT10 protein.We demon-strate that the conserved“VLD”residues and“double-E loop”are essential for enzymatic activity of AtPRMT10.In addition,we show that Arg54 and Cys259 of AtPRMT10,two residues unreported in animals,are also important for its enzymatic activity.We find that Arg13 of AtPRMT10 is the auto-methylation site.However,substitution of Arg13 to Lys13 does not affect its enzymatic activity.In vivo complementation assays reveal that plants expressing AtPRMT10 with VLD-AAA,E143Q or E152Q mutations retain high levels of FLC expression and fail to rescue the late-flowering phenotype of atprmt10 plants.Taken together,we conclude that the methyltransferase activity of AtPRMT10 is essential for repressing FLC expression and promoting flowering in Arabidopsis.
