6ahd

Structural highlights

Disease

[U5S1_HUMAN] Mandibulofacial dysostosis-microcephaly syndrome. The disease is caused by mutations affecting the gene represented in this entry. [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.^{[1] [2]} [:]^{[3] [4]} [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.^{[5] [6] [7] [8] [9]} [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.^{[10] [11] [12]} [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.

Function

[SF3A3_HUMAN] Subunit of the splicing factor SF3A required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. [SF3A2_HUMAN] Subunit of the splicing factor SF3A required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. [WBP4_HUMAN] Promotes pre-mRNA splicing. A spliceosome-associated protein; may play a role in cross-intron bridging of U1 and U2 snRNPs in the mammalian A complex.^{[13] [14]} [U5S1_HUMAN] Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing. Binds GTP. [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. [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. [RU2B_HUMAN] Involved in pre-mRNA splicing. This protein is associated with snRNP U2. It binds stem loop IV of U2 snRNA only in presence of the U2A' protein. [PR38A_HUMAN] May be required for pre-mRNA splicing. [LSM8_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [SMD1_HUMAN] May act as a charged protein scaffold to promote snRNP assembly or strengthen snRNP-snRNP interactions through nonspecific electrostatic contacts with RNA. [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.^[15] [MFAP1_HUMAN] Component of the elastin-associated microfibrils. [PRP31_HUMAN] Involved in pre-mRNA splicing. Required for U4/U6.U5 tri-snRNP formation.^[16] [SF3A1_HUMAN] Subunit of the splicing factor SF3A required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. [LSM3_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [SNUT1_HUMAN] Plays a role in mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome. May also bind to DNA.^[17] [PPIH_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex. May act as a chaperone.^{[18] [19] [20]} [PRP4_HUMAN] Involved in pre-mRNA splicing. [RU2A_HUMAN] This protein is associated with sn-RNP U2. It helps the A' protein to bind stem loop IV of U2 snRNA. [TXN4A_HUMAN] Essential role in pre-mRNA splicing. [SF3B3_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron. [LSM7_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [LSM4_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [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.^{[21] [22]} [SF3B6_HUMAN] Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA (PubMed:12234937). Directly contacts the pre-mRNA branch site adenosine for the first catalytic step of splicing (PubMed:16432215). Enters the spliceosome and associates with the pre-mRNA branch site as part of the 17S U2 or, in the case of the minor spliceosome, as part of the 18S U11/U12 snRNP complex, and thus may facilitate the interaction of these snRNP with the branch sites of U2 and U12 respectively (PubMed:16432215).^{[23] [24] [25]} [PRPF3_HUMAN] Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex. [SF3B1_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron. [SMD2_HUMAN] Required for pre-mRNA splicing. Required for snRNP biogenesis (By similarity). [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.^[26] [PHF5A_HUMAN] Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha. Also involved in pre-mRNA splicing.^[27] [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). [LSM2_HUMAN] Binds specifically to the 3'-terminal U-tract of U6 snRNA. May be involved in pre-mRNA splicing. [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. [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.^[28]

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ Bedford MT, Reed R, Leder P. WW domain-mediated interactions reveal a spliceosome-associated protein that binds a third class of proline-rich motif: the proline glycine and methionine-rich motif. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10602-7. PMID:9724750
14. ↑ Huang X, Beullens M, Zhang J, Zhou Y, Nicolaescu E, Lesage B, Hu Q, Wu J, Bollen M, Shi Y. Structure and function of the two tandem WW domains of the pre-mRNA splicing factor FBP21 (formin-binding protein 21). J Biol Chem. 2009 Sep 11;284(37):25375-87. Epub 2009 Jul 10. PMID:19592703 doi:10.1074/jbc.M109.024828
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ Teigelkamp S, Achsel T, Mundt C, Gothel SF, Cronshagen U, Lane WS, Marahiel M, Luhrmann R. The 20kD protein of human [U4/U6.U5] tri-snRNPs is a novel cyclophilin that forms a complex with the U4/U6-specific 60kD and 90kD proteins. RNA. 1998 Feb;4(2):127-41. PMID:9570313
19. ↑ Horowitz DS, Lee EJ, Mabon SA, Misteli T. A cyclophilin functions in pre-mRNA splicing. EMBO J. 2002 Feb 1;21(3):470-80. PMID:11823439
20. ↑ Reidt U, Wahl MC, Fasshauer D, Horowitz DS, Luhrmann R, Ficner R. Crystal structure of a complex between human spliceosomal cyclophilin H and a U4/U6 snRNP-60K peptide. J Mol Biol. 2003 Aug 1;331(1):45-56. PMID:12875835
21. ↑ 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
22. ↑ 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
23. ↑ Will CL, Urlaub H, Achsel T, Gentzel M, Wilm M, Luhrmann R. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002 Sep 16;21(18):4978-88. PMID:12234937
24. ↑ Schellenberg MJ, Edwards RA, Ritchie DB, Kent OA, Golas MM, Stark H, Luhrmann R, Glover JN, MacMillan AM. Crystal structure of a core spliceosomal protein interface. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1266-71. Epub 2006 Jan 23. PMID:16432215
25. ↑ Cretu C, Schmitzova J, Ponce-Salvatierra A, Dybkov O, De Laurentiis EI, Sharma K, Will CL, Urlaub H, Luhrmann R, Pena V. Molecular Architecture of SF3b and Structural Consequences of Its Cancer-Related Mutations. Mol Cell. 2016 Oct 20;64(2):307-319. doi: 10.1016/j.molcel.2016.08.036. Epub 2016, Oct 6. PMID:27720643 doi:http://dx.doi.org/10.1016/j.molcel.2016.08.036
26. ↑ 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
27. ↑ Will CL, Urlaub H, Achsel T, Gentzel M, Wilm M, Luhrmann R. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002 Sep 16;21(18):4978-88. PMID:12234937
28. ↑ 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
29. ↑ Zhan X, Yan C, Zhang X, Lei J, Shi Y. Structures of the human pre-catalytic spliceosome and its precursor spliceosome. Cell Res. 2018 Oct 12. pii: 10.1038/s41422-018-0094-7. doi:, 10.1038/s41422-018-0094-7. PMID:30315277 doi:http://dx.doi.org/10.1038/s41422-018-0094-7