人PRMT5基因的生物信息学分析
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摘要
PRMT5 (Protein arginine methyltransferase 5)已经广泛地作为组蛋白甲基转移酶修饰H4R3、H2AR3和H3R8,从而潜在地影响多个信号传导途径。本研究为了对人PRMT5基因进行生物信息学方面的深入分析,以PRMT5基因序列及编码蛋白序列为材料,通过生物信息学方法分析了PRMT5基因的DNA序列、启动子及CpG岛、RNA结构,及该蛋白的理化性质、亚细胞定位、信号肽与跨膜区域、互作蛋白、系统发育等。研究结果表明,人PRMT5在物种间的保守性相对较高,位于染色体14q11.2,大小为1 911 bp,潜在核心启动子在1 014～1 064 bp,没有预测到CpG岛。PRMT5基因编码637个氨基酸残基,分子量为10 157 Da,等电点为5.88,不稳定系数是44.33;该蛋白更可能定位于细胞质,无明显的信号肽及跨膜结构;主要的二级结构元件是α-螺旋结构和无规卷曲,包含一个SAM-dependent MTase功能结构域,同时有10个可能的互作蛋白;进化分析表明黑猩猩和猕猴与人PRMT5蛋白亲缘关系最近。
PRMT5(Protein Arginine Methyltransferase 5) had been extensively characterized as a histone methyltransferase that modifies H4 R3, H2 AR3 and H3 R8, and affects potential multiple signaling pathways. In this research, the nucleotide and encoded protein sequence of PRMT5 were used as materials in order to further analyze bioinformatics of human PRMT5 gene. The nucleic acid sequence and amino acid sequence of PRMT5 gene were analyzed and predicted by bioinformatics approaches, including DNA sequence, promoter and CpG island and RNA structure, physicochemical properties, the subcellular position, signal peptide, transmembrane region, protein interaction networks and evolutionary tree. The results showed that PRMT5 are relatively conserved among species, located on chromosome 14 q11.2, with a size of 1 911 bp. The potential core promoter is located at 1 014～1 064 bp and no CpG island was predicted. The PRMT5 gene encodes 637 amino acid residues with a molecular weight of 10 157 Da, an isoelectric point of 5.88 and an instability coefficient of44.33. The protein is more likely localized in the cytoplasm with no obvious signal peptide and transmembrane structure. The major secondary structure elements are an α-helical structure and a random coil, which contains a SAM-dependent MTase functional domain with 10 possible interacting proteins. Phylogenetic analysis shows that Chimpanzees and Macaques have the closest relationship with human PRMT5 protein.
PRMT5(Protein Arginine Methyltransferase 5) had been extensively characterized as a histone methyltransferase that modifies H4 R3, H2 AR3 and H3 R8, and affects potential multiple signaling pathways. In this research, the nucleotide and encoded protein sequence of PRMT5 were used as materials in order to further analyze bioinformatics of human PRMT5 gene. The nucleic acid sequence and amino acid sequence of PRMT5 gene were analyzed and predicted by bioinformatics approaches, including DNA sequence, promoter and CpG island and RNA structure, physicochemical properties, the subcellular position, signal peptide, transmembrane region, protein interaction networks and evolutionary tree. The results showed that PRMT5 are relatively conserved among species, located on chromosome 14 q11.2, with a size of 1 911 bp. The potential core promoter is located at 1 014～1 064 bp and no CpG island was predicted. The PRMT5 gene encodes 637 amino acid residues with a molecular weight of 10 157 Da, an isoelectric point of 5.88 and an instability coefficient of44.33. The protein is more likely localized in the cytoplasm with no obvious signal peptide and transmembrane structure. The major secondary structure elements are an α-helical structure and a random coil, which contains a SAM-dependent MTase functional domain with 10 possible interacting proteins. Phylogenetic analysis shows that Chimpanzees and Macaques have the closest relationship with human PRMT5 protein.
引文
Bedford M.T.,and Clarke S.G.,2009,Protein arginine methylation in mammals:who,what,and why,Mol.Cell,33(1):1-13
Bedford T.L.,Frankel A.,Lee J.H.,Cook J.R.,Yang A.H.,Pestka S.,and Clarke S.,2001,PRMT5(Janus kinase-binding protein 1)catalyzes the formation of symmetric dimthylarginine residues in proteins,J.Biol.Chem.,276(35):32971-32976
Chen H.,Lorton B.,Gupta V.,and Shechter D.,2017,A TGFbetaPRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression,Oncogene,36(3):373-386
Kanda M.,Shimizu D.,Fujii T.,Tanaka H.,Shibata M.,Iwata N.Hayashi M.,Kobayashi D.,Tanaka C.,Yamada S.,Nakaya ma G.,Sugimoto H.,Koike M.,Fujiwara M.,and Kodera Y.2016,Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer,Int.J.Oncol.,49(3):1195-1202
Kaushik S.,Liu F.,Veazey K.J.,Gao G.,Das P.,Neves L.F.,Lin K.,Zhong Y.,Lu Y.,Giuliani V.,Bedford M.T.,Nimer S.D.and Santos M.A.,2017,Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibi anti-tumoral activity in mouse models of MLL-rearranged AML,Leukemia.,206:1-31
Kim S.,Gunesdogan U.,Zylicz J.J.,Hackett J.A.,Cougot D.,Bao S.,Lee C.,Dietmann S.,Allen G.E.,Sengupta R.,and Surani M.A.,2014,PRMT5 protects genomic integrity during global DNA demeth ylation in primordial germ cells and preimplantation embryos,Mol.Cell,56(4):564-579
Krause C.D.,Yamg Z.H.,Kim Y.S.,Lee J.K.,Cook J.R.,and Pestka S.,2007,Protein arginine methyltransferases:evolution and assessment of their pharmacological and therapeutic protential,Pharmacol.Ther.,113(1):50-87
Liu L.,Zhao X.P.,Zhao L.,Li J.J.,Yang H.,Zhu Z.P.,Liu J.J.,and Huang G.,2016,Arginine methylation of SREBP1a via PRMT5 promotes de novo lipogenesis and tumor growth,Cancer Res.,76(5):1260-1272
Nicholas C.,Yang J.,Peters S.B.,Bill M.A.,Baiocchi R.A.,Yan F.,S?f S.,Tae S.,Gaudio E.,Wu X.,Grever M.R.,Yong G.S.,and Lesinski G.B.,2013,PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1),PLoS One,8(9):e74710
Pal S.,Vishwanath S.N.,Erdjument-Bromage H.,Tempst P.,and Sif S.,2004,Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes,Mol.Cell.Biol.,24(21):9630-9645
Rengasamy M.,Zhang F.,Vashisht A.,Song W.M.,Aguilo F.,Sun Y.,Li S.,Zhang W.,Zhang B.,Wohlschlegel J.A.,and Walsh M.J.,2017,The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer,Nucleic Acids Res.,45(19):11106-11120
Wang L.,Pal S.,and Sif S.,2008,Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells,Mol.Cell.Biol.,28(20):6262-6277
Zhang B.,Dong S.,Zhu R.,Hu C.,Hou J.,Li Y.,Zhao Q.,Shao X.,Bu Q.,Li H.,Wu Y.,Cen X.,and Zhao Y.,2015,Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4Eand FGFR3,Oncotarget,6(26):22799-22811
Zheng Y.X.,Huang L.Y.,Ge W.S.,Yang M.,Ma Y.H.,Xie G.H.,Wang W.W.,Bian B.X.,Li L.,Nie H.,and Shen L.S.,2017,Protein arginine methyltransferase 5 inhibition upregulates Foxp3+regulatory T cells frequency and function during the ulcerative colitis,Front.Immunol,8:596
Bedford T.L.,Frankel A.,Lee J.H.,Cook J.R.,Yang A.H.,Pestka S.,and Clarke S.,2001,PRMT5(Janus kinase-binding protein 1)catalyzes the formation of symmetric dimthylarginine residues in proteins,J.Biol.Chem.,276(35):32971-32976
Chen H.,Lorton B.,Gupta V.,and Shechter D.,2017,A TGFbetaPRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression,Oncogene,36(3):373-386
Kanda M.,Shimizu D.,Fujii T.,Tanaka H.,Shibata M.,Iwata N.Hayashi M.,Kobayashi D.,Tanaka C.,Yamada S.,Nakaya ma G.,Sugimoto H.,Koike M.,Fujiwara M.,and Kodera Y.2016,Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer,Int.J.Oncol.,49(3):1195-1202
Kaushik S.,Liu F.,Veazey K.J.,Gao G.,Das P.,Neves L.F.,Lin K.,Zhong Y.,Lu Y.,Giuliani V.,Bedford M.T.,Nimer S.D.and Santos M.A.,2017,Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibi anti-tumoral activity in mouse models of MLL-rearranged AML,Leukemia.,206:1-31
Kim S.,Gunesdogan U.,Zylicz J.J.,Hackett J.A.,Cougot D.,Bao S.,Lee C.,Dietmann S.,Allen G.E.,Sengupta R.,and Surani M.A.,2014,PRMT5 protects genomic integrity during global DNA demeth ylation in primordial germ cells and preimplantation embryos,Mol.Cell,56(4):564-579
Krause C.D.,Yamg Z.H.,Kim Y.S.,Lee J.K.,Cook J.R.,and Pestka S.,2007,Protein arginine methyltransferases:evolution and assessment of their pharmacological and therapeutic protential,Pharmacol.Ther.,113(1):50-87
Liu L.,Zhao X.P.,Zhao L.,Li J.J.,Yang H.,Zhu Z.P.,Liu J.J.,and Huang G.,2016,Arginine methylation of SREBP1a via PRMT5 promotes de novo lipogenesis and tumor growth,Cancer Res.,76(5):1260-1272
Nicholas C.,Yang J.,Peters S.B.,Bill M.A.,Baiocchi R.A.,Yan F.,S?f S.,Tae S.,Gaudio E.,Wu X.,Grever M.R.,Yong G.S.,and Lesinski G.B.,2013,PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1),PLoS One,8(9):e74710
Pal S.,Vishwanath S.N.,Erdjument-Bromage H.,Tempst P.,and Sif S.,2004,Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes,Mol.Cell.Biol.,24(21):9630-9645
Rengasamy M.,Zhang F.,Vashisht A.,Song W.M.,Aguilo F.,Sun Y.,Li S.,Zhang W.,Zhang B.,Wohlschlegel J.A.,and Walsh M.J.,2017,The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer,Nucleic Acids Res.,45(19):11106-11120
Wang L.,Pal S.,and Sif S.,2008,Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells,Mol.Cell.Biol.,28(20):6262-6277
Zhang B.,Dong S.,Zhu R.,Hu C.,Hou J.,Li Y.,Zhao Q.,Shao X.,Bu Q.,Li H.,Wu Y.,Cen X.,and Zhao Y.,2015,Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4Eand FGFR3,Oncotarget,6(26):22799-22811
Zheng Y.X.,Huang L.Y.,Ge W.S.,Yang M.,Ma Y.H.,Xie G.H.,Wang W.W.,Bian B.X.,Li L.,Nie H.,and Shen L.S.,2017,Protein arginine methyltransferase 5 inhibition upregulates Foxp3+regulatory T cells frequency and function during the ulcerative colitis,Front.Immunol,8:596