3jcr

Structural highlights

Disease

[U5S1_HUMAN] Mandibulofacial dysostosis-microcephaly syndrome. The disease is caused by mutations affecting the gene represented in this entry. [PRPF3_HUMAN] Defects in PRPF3 are the cause of retinitis pigmentosa type 18 (RP18) [MIM:601414]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP18 inheritance is autosomal dominant.^{[1] [2] [3]} [PRP6_HUMAN] Retinitis pigmentosa. The disease may be caused by mutations affecting the gene represented in this entry. Cells from RP60 patients show intron retention for pre-mRNA bearing specific splicing signals. [U520_HUMAN] Retinitis pigmentosa. Retinitis pigmentosa 33 (RP33) [MIM:610359]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note=The disease is caused by mutations affecting the gene represented in this entry.^{[4] [5] [6] [7] [8]} [PRP31_HUMAN] Defects in PRPF31 are the cause of retinitis pigmentosa type 11 (RP11) [MIM:600138]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP11 inheritance is autosomal dominant.^{[9] [10] [11] [12] [13]} [PRP8_HUMAN] Defects in PRPF8 are the cause of retinitis pigmentosa type 13 (RP13) [MIM:600059]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP13 inheritance is autosomal dominant.^{[14] [15]} [:]^{[16] [17]}

Function

[SMD3_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Binds to the downstream cleavage product (DCP) of histone pre-mRNA in a U7 snRNP dependent manner.^[18] [LSM7_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [U5S1_HUMAN] Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing. Binds GTP. [SNUT2_HUMAN] Plays a role in pre-mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome. Regulates AURKB mRNA levels, and thereby plays a role in cytokinesis and in the spindle checkpoint. Does not have ubiquitin-specific peptidase activity, but could be a competitor of ubiquitin C-terminal hydrolases (UCHs).^{[19] [20]} [SNR40_HUMAN] Component of the U5 small nuclear ribonucleoprotein (snRNP) complex. The U5 snRNP is part of the spliceosome, a multiprotein complex that catalyzes the removal of introns from pre-messenger RNAs.^[21] [LSM5_HUMAN] Plays a role in U6 snRNP assembly and function. Binds to the 3' end of U6 snRNA, thereby facilitating formation of the spliceosomal U4/U6 duplex formation in vitro. [PRPF3_HUMAN] Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex. [PRP6_HUMAN] Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome. Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation.^[22] [LSM4_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [RUXF_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Associated with snRNP U1, U2, U4/U6 and U5. [LSM6_HUMAN] Component of LSm protein complexes, which are involved in RNA processing and may function in a chaperone-like manner, facilitating the efficient association of RNA processing factors with their substrates. Component of the cytoplasmic LSM1-LSM7 complex, which is thought to be involved in mRNA degradation by activating the decapping step in the 5'-to-3' mRNA decay pathway. Component of the nuclear LSM2-LSM8 complex, which is involved in splicing of nuclear mRNAs. LSM2-LSM8 associates with multiple snRNP complexes containing the U6 snRNA (U4/U6 di-snRNP, spliceosomal U4/U6.U5 tri-snRNP, and free U6 snRNP). It binds directly to the 3'-terminal U-tract of U6 snRNA and plays a role in the biogenesis and stability of the U6 snRNP and U4/U6 snRNP complexes. LSM2-LSM8 probably also is involved degradation of nuclear pre-mRNA by targeting them for decapping, and in processing of pre-tRNAs, pre-rRNAs and U3 snoRNA (By similarity). [DDX23_HUMAN] Involved in pre-mRNA splicing and its phosphorylated form (by SRPK2) is required for spliceosomal B complex formation.^[23] [NH2L1_HUMAN] Binds to the 5'-stem-loop of U4 snRNA and may play a role in the late stage of spliceosome assembly. The protein undergoes a conformational change upon RNA-binding.^{[24] [25]} [U520_HUMAN] RNA helicase that plays an essential role in pre-mRNA splicing as component of the U5 snRNP and U4/U6-U5 tri-snRNP complexes. Involved in spliceosome assembly, activation and disassembly. Mediates changes in the dynamic network of RNA-RNA interactions in the spliceosome. Catalyzes the ATP-dependent unwinding of U4/U6 RNA duplices, an essential step in the assembly of a catalytically active spliceosome.^{[26] [27] [28] [29]} [SMD1_HUMAN] May act as a charged protein scaffold to promote snRNP assembly or strengthen snRNP-snRNP interactions through nonspecific electrostatic contacts with RNA. [RUXE_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Associated with snRNP U1, U2, U4/U6 and U5. [RUXG_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Associated with snRNP U1, U2, U4/U6 and U5. [LSM8_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [LSM2_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. May be involved in pre-mRNA splicing. [RSMB_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Associated with snRNP U1, U2, U4/U6 and U5. May have a functional role in the pre-mRNA splicing or in snRNP structure. Binds to the downstream cleavage product (DCP) of histone pre-mRNA in a U7 snRNP dependent manner (By similarity). [TXN4A_HUMAN] Essential role in pre-mRNA splicing. [PRP31_HUMAN] Involved in pre-mRNA splicing. Required for U4/U6.U5 tri-snRNP formation.^[30] [SMD2_HUMAN] Required for pre-mRNA splicing. Required for snRNP biogenesis (By similarity). [LSM3_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [PRP8_HUMAN] Central component of the spliceosome, which may play a role in aligning the pre-mRNA 5'- and 3'-exons for ligation. Interacts with U5 snRNA, and with pre-mRNA 5'-splice sites in B spliceosomes and 3'-splice sites in C spliceosomes.

References

1. ↑ Chakarova CF, Hims MM, Bolz H, Abu-Safieh L, Patel RJ, Papaioannou MG, Inglehearn CF, Keen TJ, Willis C, Moore AT, Rosenberg T, Webster AR, Bird AC, Gal A, Hunt D, Vithana EN, Bhattacharya SS. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. Hum Mol Genet. 2002 Jan 1;11(1):87-92. PMID:11773002
2. ↑ Martinez-Gimeno M, Gamundi MJ, Hernan I, Maseras M, Milla E, Ayuso C, Garcia-Sandoval B, Beneyto M, Vilela C, Baiget M, Antinolo G, Carballo M. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7. PMID:12714658
3. ↑ Gonzalez-Santos JM, Cao H, Duan RC, Hu J. Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex. Hum Mol Genet. 2008 Jan 15;17(2):225-39. Epub 2007 Oct 11. PMID:17932117 doi:ddm300
4. ↑ Liu S, Rauhut R, Vornlocher HP, Luhrmann R. The network of protein-protein interactions within the human U4/U6.U5 tri-snRNP. RNA. 2006 Jul;12(7):1418-30. Epub 2006 May 24. PMID:16723661 doi:rna.55406
5. ↑ Santos KF, Jovin SM, Weber G, Pena V, Luhrmann R, Wahl MC. Structural basis for functional cooperation between tandem helicase cassettes in Brr2-mediated remodeling of the spliceosome. Proc Natl Acad Sci U S A. 2012 Oct 8. PMID:23045696 doi:10.1073/pnas.1208098109
6. ↑ Zhao C, Bellur DL, Lu S, Zhao F, Grassi MA, Bowne SJ, Sullivan LS, Daiger SP, Chen LJ, Pang CP, Zhao K, Staley JP, Larsson C. Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. Am J Hum Genet. 2009 Nov;85(5):617-27. Epub 2009 Oct 29. PMID:19878916 doi:S0002-9297(09)00455-8
7. ↑ Li N, Mei H, MacDonald IM, Jiao X, Hejtmancik JF. Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family. Invest Ophthalmol Vis Sci. 2010 Feb;51(2):1036-43. doi: 10.1167/iovs.09-3725., Epub 2009 Aug 26. PMID:19710410 doi:10.1167/iovs.09-3725
8. ↑ Benaglio P, McGee TL, Capelli LP, Harper S, Berson EL, Rivolta C. Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa. Hum Mutat. 2011 Jun;32(6):E2246-58. doi: 10.1002/humu.21485. Epub 2011 Feb 24. PMID:21618346 doi:10.1002/humu.21485
9. ↑ Liu S, Li P, Dybkov O, Nottrott S, Hartmuth K, Luhrmann R, Carlomagno T, Wahl MC. Binding of the human Prp31 Nop domain to a composite RNA-protein platform in U4 snRNP. Science. 2007 Apr 6;316(5821):115-20. PMID:17412961 doi:316/5821/115
10. ↑ Deery EC, Vithana EN, Newbold RJ, Gallon VA, Bhattacharya SS, Warren MJ, Hunt DM, Wilkie SE. Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31. Hum Mol Genet. 2002 Dec 1;11(25):3209-19. PMID:12444105
11. ↑ Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001 Aug;8(2):375-81. PMID:11545739
12. ↑ Al-Maghtheh M, Vithana E, Tarttelin E, Jay M, Evans K, Moore T, Bhattacharya S, Inglehearn CF. Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype. Am J Hum Genet. 1996 Oct;59(4):864-71. PMID:8808602
13. ↑ Wang L, Ribaudo M, Zhao K, Yu N, Chen Q, Sun Q, Wang L, Wang Q. Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family. Am J Med Genet A. 2003 Sep 1;121A(3):235-9. PMID:12923864 doi:http://dx.doi.org/10.1002/ajmg.a.20224
14. ↑ Pena V, Liu S, Bujnicki JM, Luhrmann R, Wahl MC. Structure of a multipartite protein-protein interaction domain in splicing factor prp8 and its link to retinitis pigmentosa. Mol Cell. 2007 Feb 23;25(4):615-24. PMID:17317632 doi:10.1016/j.molcel.2007.01.023
15. ↑ McKie AB, McHale JC, Keen TJ, Tarttelin EE, Goliath R, van Lith-Verhoeven JJ, Greenberg J, Ramesar RS, Hoyng CB, Cremers FP, Mackey DA, Bhattacharya SS, Bird AC, Markham AF, Inglehearn CF. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet. 2001 Jul 15;10(15):1555-62. PMID:11468273
16. ↑ van Lith-Verhoeven JJ, van der Velde-Visser SD, Sohocki MM, Deutman AF, Brink HM, Cremers FP, Hoyng CB. Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13). Ophthalmic Genet. 2002 Mar;23(1):1-12. PMID:11910553
17. ↑ Martinez-Gimeno M, Gamundi MJ, Hernan I, Maseras M, Milla E, Ayuso C, Garcia-Sandoval B, Beneyto M, Vilela C, Baiget M, Antinolo G, Carballo M. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7. PMID:12714658
18. ↑ Pillai RS, Will CL, Luhrmann R, Schumperli D, Muller B. Purified U7 snRNPs lack the Sm proteins D1 and D2 but contain Lsm10, a new 14 kDa Sm D1-like protein. EMBO J. 2001 Oct 1;20(19):5470-9. PMID:11574479 doi:10.1093/emboj/20.19.5470
19. ↑ Makarova OV, Makarov EM, Luhrmann R. The 65 and 110 kDa SR-related proteins of the U4/U6.U5 tri-snRNP are essential for the assembly of mature spliceosomes. EMBO J. 2001 May 15;20(10):2553-63. PMID:11350945 doi:http://dx.doi.org/10.1093/emboj/20.10.2553
20. ↑ van Leuken RJ, Luna-Vargas MP, Sixma TK, Wolthuis RM, Medema RH. Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B. Cell Cycle. 2008 Sep 1;7(17):2710-9. Epub 2008 Sep 3. PMID:18728397
21. ↑ Achsel T, Ahrens K, Brahms H, Teigelkamp S, Luhrmann R. The human U5-220kD protein (hPrp8) forms a stable RNA-free complex with several U5-specific proteins, including an RNA unwindase, a homologue of ribosomal elongation factor EF-2, and a novel WD-40 protein. Mol Cell Biol. 1998 Nov;18(11):6756-66. PMID:9774689
22. ↑ Zhao Y, Goto K, Saitoh M, Yanase T, Nomura M, Okabe T, Takayanagi R, Nawata H. Activation function-1 domain of androgen receptor contributes to the interaction between subnuclear splicing factor compartment and nuclear receptor compartment. Identification of the p102 U5 small nuclear ribonucleoprotein particle-binding protein as a coactivator for the receptor. J Biol Chem. 2002 Aug 16;277(33):30031-9. Epub 2002 May 30. PMID:12039962 doi:http://dx.doi.org/10.1074/jbc.M203811200
23. ↑ Mathew R, Hartmuth K, Mohlmann S, Urlaub H, Ficner R, Luhrmann R. Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome. Nat Struct Mol Biol. 2008 May;15(5):435-43. doi: 10.1038/nsmb.1415. Epub 2008 Apr, 20. PMID:18425142 doi:http://dx.doi.org/10.1038/nsmb.1415
24. ↑ Nottrott S, Hartmuth K, Fabrizio P, Urlaub H, Vidovic I, Ficner R, Luhrmann R. Functional interaction of a novel 15.5kD [U4/U6.U5] tri-snRNP protein with the 5' stem-loop of U4 snRNA. EMBO J. 1999 Nov 1;18(21):6119-33. PMID:10545122 doi:10.1093/emboj/18.21.6119
25. ↑ Liu S, Li P, Dybkov O, Nottrott S, Hartmuth K, Luhrmann R, Carlomagno T, Wahl MC. Binding of the human Prp31 Nop domain to a composite RNA-protein platform in U4 snRNP. Science. 2007 Apr 6;316(5821):115-20. PMID:17412961 doi:316/5821/115
26. ↑ Liu S, Rauhut R, Vornlocher HP, Luhrmann R. The network of protein-protein interactions within the human U4/U6.U5 tri-snRNP. RNA. 2006 Jul;12(7):1418-30. Epub 2006 May 24. PMID:16723661 doi:rna.55406
27. ↑ Lauber J, Fabrizio P, Teigelkamp S, Lane WS, Hartmann E, Luhrmann R. The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases. EMBO J. 1996 Aug 1;15(15):4001-15. PMID:8670905
28. ↑ Laggerbauer B, Achsel T, Luhrmann R. The human U5-200kD DEXH-box protein unwinds U4/U6 RNA duplices in vitro. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4188-92. PMID:9539711
29. ↑ Santos KF, Jovin SM, Weber G, Pena V, Luhrmann R, Wahl MC. Structural basis for functional cooperation between tandem helicase cassettes in Brr2-mediated remodeling of the spliceosome. Proc Natl Acad Sci U S A. 2012 Oct 8. PMID:23045696 doi:10.1073/pnas.1208098109
30. ↑ Makarova OV, Makarov EM, Liu S, Vornlocher HP, Luhrmann R. Protein 61K, encoded by a gene (PRPF31) linked to autosomal dominant retinitis pigmentosa, is required for U4/U6*U5 tri-snRNP formation and pre-mRNA splicing. EMBO J. 2002 Mar 1;21(5):1148-57. PMID:11867543 doi:10.1093/emboj/21.5.1148
31. ↑ Agafonov DE, Kastner B, Dybkov O, Hofele RV, Liu WT, Urlaub H, Luhrmann R, Stark H. Molecular architecture of the human U4/U6.U5 tri-snRNP. Science. 2016 Feb 18. pii: aad2085. PMID:26912367 doi:http://dx.doi.org/10.1126/science.aad2085