| Structural highlights
Disease
[R113A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. [CDC5L_HUMAN] Note=A chromosomal aberration involving CDC5L is found in multicystic renal dysplasia. Translocation t(6;19)(p21;q13.1) with USF2. [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]
Function
[PLRG1_HUMAN] Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. [SF3B2_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. [CWC15_HUMAN] Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing.[5] [CWC27_HUMAN] PPIases accelerate the folding of proteins. [SRRM2_HUMAN] Involved in pre-mRNA splicing. May function at or prior to the first catalytic step of splicing at the catalytic center of the spliceosome. May do so by stabilizing the catalytic center or the position of the RNA substrate (By similarity). Binds to RNA.[6] [CDC5L_HUMAN] DNA-binding protein involved in cell cycle control. May act as a transcription activator. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing.[7] [8] [9] [10] [11] [12] [13] [14] [15] [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.[16] [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. [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. [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).[17] [18] [19] [U5S1_HUMAN] Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing. Binds GTP. [PRP17_HUMAN] Associates with the spliceosome late in the splicing pathway and may function in the second step of pre-mRNA splicing.[20] [SRRM1_HUMAN] Part of pre- and post-splicing multiprotein mRNP complexes. Involved in numerous pre-mRNA processing events. Promotes constitutive and exonic splicing enhancer (ESE)-dependent splicing activation by bridging together sequence-specific (SR family proteins, SFRS4, SFRS5 and TRA2B/SFRS10) and basal snRNP (SNRP70 and SNRPA1) factors of the spliceosome. Stimulates mRNA 3'-end cleavage independently of the formation of an exon junction complex. Binds both pre-mRNA and spliced mRNA 20-25 nt upstream of exon-exon junctions. Binds RNA and DNA with low sequence specificity and has similar preference for either double- or single-stranded nucleic acid substrates.[21] [22] [23] [24] [25] [26] [CRNL1_HUMAN] Involved in pre-mRNA splicing process. [RBM22_HUMAN] Involved in the first step of pre-mRNA splicing. Binds directly to the internal stem-loop (ISL) domain of the U6 snRNA and to the pre-mRNA intron near the 5' splice site during the activation and catalytic phases of the spliceosome cycle. Involved in both translocations of the nuclear SLU7 to the cytoplasm and the cytosolic calcium-binding protein PDCD6 to the nucleus upon cellular stress responses.[27] [28] [29] [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. [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. [PPIL1_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. May be involved in pre-mRNA splicing.[30] [SNW1_HUMAN] Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD. Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters. Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter. Functions as a splicing factor in pre-mRNA splicing. Is required in the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. Is proposed to recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA.[31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]
Publication Abstract from PubMed
The spliceosome is a highly dynamic macromolecular complex that precisely excises introns from pre-mRNA. Here we report the cryo-EM 3D structure of the human B(act) spliceosome at 3.4 A resolution. In the B(act) state, the spliceosome is activated but not catalytically primed, so that it is functionally blocked prior to the first catalytic step of splicing. The spliceosomal core is similar to the yeast B(act) spliceosome; important differences include the presence of the RNA helicase aquarius and peptidyl prolyl isomerases. To examine the overall dynamic behavior of the purified spliceosome, we developed a principal component analysis-based approach. Calculating the energy landscape revealed eight major conformational states, which we refined to higher resolution. Conformational differences of the highly flexible structural components between these eight states reveal how spliceosomal components contribute to the assembly of the spliceosome, allowing it to generate a dynamic interaction network required for its subsequent catalytic activation.
Structure and Conformational Dynamics of the Human Spliceosomal B(act) Complex.,Haselbach D, Komarov I, Agafonov DE, Hartmuth K, Graf B, Dybkov O, Urlaub H, Kastner B, Luhrmann R, Stark H Cell. 2018 Jan 25;172(3):454-464.e11. doi: 10.1016/j.cell.2018.01.010. Epub 2018 , Jan 17. PMID:29361316[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Grote M, Wolf E, Will CL, Lemm I, Agafonov DE, Schomburg A, Fischle W, Urlaub H, Luhrmann R. Molecular architecture of the human Prp19/CDC5L complex. Mol Cell Biol. 2010 May;30(9):2105-19. doi: 10.1128/MCB.01505-09. Epub 2010 Feb, 22. PMID:20176811 doi:http://dx.doi.org/10.1128/MCB.01505-09
- ↑ Blencowe BJ, Bauren G, Eldridge AG, Issner R, Nickerson JA, Rosonina E, Sharp PA. The SRm160/300 splicing coactivator subunits. RNA. 2000 Jan;6(1):111-20. PMID:10668804
- ↑ Bernstein HS, Coughlin SR. Pombe Cdc5-related protein. A putative human transcription factor implicated in mitogen-activated signaling. J Biol Chem. 1997 Feb 28;272(9):5833-7. PMID:9038199
- ↑ Ohi R, Feoktistova A, McCann S, Valentine V, Look AT, Lipsick JS, Gould KL. Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes. Mol Cell Biol. 1998 Jul;18(7):4097-108. PMID:9632794
- ↑ Bernstein HS, Coughlin SR. A mammalian homolog of fission yeast Cdc5 regulates G2 progression and mitotic entry. J Biol Chem. 1998 Feb 20;273(8):4666-71. PMID:9468527
- ↑ Burns CG, Ohi R, Krainer AR, Gould KL. Evidence that Myb-related CDC5 proteins are required for pre-mRNA splicing. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13789-94. PMID:10570151
- ↑ Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI. Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry. EMBO J. 2000 Dec 1;19(23):6569-81. PMID:11101529 doi:10.1093/emboj/19.23.6569
- ↑ Lei XH, Shen X, Xu XQ, Bernstein HS. Human Cdc5, a regulator of mitotic entry, can act as a site-specific DNA binding protein. J Cell Sci. 2000 Dec;113 Pt 24:4523-31. PMID:11082045
- ↑ Ajuh P, Sleeman J, Chusainow J, Lamond AI. A direct interaction between the carboxyl-terminal region of CDC5L and the WD40 domain of PLRG1 is essential for pre-mRNA splicing. J Biol Chem. 2001 Nov 9;276(45):42370-81. Epub 2001 Sep 5. PMID:11544257 doi:10.1074/jbc.M105453200
- ↑ Leonard D, Ajuh P, Lamond AI, Legerski RJ. hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing. Biochem Biophys Res Commun. 2003 Sep 5;308(4):793-801. PMID:12927788
- ↑ Graub R, Lancero H, Pedersen A, Chu M, Padmanabhan K, Xu XQ, Spitz P, Chalkley R, Burlingame AL, Stokoe D, Bernstein HS. Cell cycle-dependent phosphorylation of human CDC5 regulates RNA processing. Cell Cycle. 2008 Jun 15;7(12):1795-803. Epub 2008 Jun 25. PMID:18583928
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Lindsey LA, Garcia-Blanco MA. Functional conservation of the human homolog of the yeast pre-mRNA splicing factor Prp17p. J Biol Chem. 1998 Dec 4;273(49):32771-5. PMID:9830021
- ↑ Blencowe BJ, Issner R, Nickerson JA, Sharp PA. A coactivator of pre-mRNA splicing. Genes Dev. 1998 Apr 1;12(7):996-1009. PMID:9531537
- ↑ Eldridge AG, Li Y, Sharp PA, Blencowe BJ. The SRm160/300 splicing coactivator is required for exon-enhancer function. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6125-30. PMID:10339552
- ↑ Blencowe BJ, Bauren G, Eldridge AG, Issner R, Nickerson JA, Rosonina E, Sharp PA. The SRm160/300 splicing coactivator subunits. RNA. 2000 Jan;6(1):111-20. PMID:10668804
- ↑ McCracken S, Lambermon M, Blencowe BJ. SRm160 splicing coactivator promotes transcript 3'-end cleavage. Mol Cell Biol. 2002 Jan;22(1):148-60. PMID:11739730
- ↑ McCracken S, Longman D, Johnstone IL, Caceres JF, Blencowe BJ. An evolutionarily conserved role for SRm160 in 3'-end processing that functions independently of exon junction complex formation. J Biol Chem. 2003 Nov 7;278(45):44153-60. Epub 2003 Aug 27. PMID:12944400 doi:http://dx.doi.org/10.1074/jbc.M306856200
- ↑ Szymczyna BR, Bowman J, McCracken S, Pineda-Lucena A, Lu Y, Cox B, Lambermon M, Graveley BR, Arrowsmith CH, Blencowe BJ. Structure and function of the PWI motif: a novel nucleic acid-binding domain that facilitates pre-mRNA processing. Genes Dev. 2003 Feb 15;17(4):461-75. PMID:12600940 doi:10.1101/gad.1060403
- ↑ Montaville P, Dai Y, Cheung CY, Giller K, Becker S, Michalak M, Webb SE, Miller AL, Krebs J. Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochim Biophys Acta. 2006 Nov;1763(11):1335-43. Epub 2006 Sep 14. PMID:17045351 doi:http://dx.doi.org/10.1016/j.bbamcr.2006.09.003
- ↑ Janowicz A, Michalak M, Krebs J. Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7. Biochim Biophys Acta. 2011 May;1813(5):1045-9. doi: 10.1016/j.bbamcr.2010.11.010., Epub 2010 Nov 29. PMID:21122810 doi:http://dx.doi.org/10.1016/j.bbamcr.2010.11.010
- ↑ Rasche N, Dybkov O, Schmitzova J, Akyildiz B, Fabrizio P, Luhrmann R. Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre. EMBO J. 2012 Mar 21;31(6):1591-604. doi: 10.1038/emboj.2011.502. Epub 2012 Jan, 13. PMID:22246180 doi:http://dx.doi.org/10.1038/emboj.2011.502
- ↑ Xu C, Zhang J, Huang X, Sun J, Xu Y, Tang Y, Wu J, Shi Y, Huang Q, Zhang Q. Solution structure of human peptidyl prolyl isomerase-like protein 1 and insights into its interaction with SKIP. J Biol Chem. 2006 Jun 9;281(23):15900-8. Epub 2006 Apr 4. PMID:16595688 doi:10.1074/jbc.M511155200
- ↑ Zhou S, Fujimuro M, Hsieh JJ, Chen L, Hayward SD. A role for SKIP in EBNA2 activation of CBF1-repressed promoters. J Virol. 2000 Feb;74(4):1939-47. PMID:10644367
- ↑ Leong GM, Subramaniam N, Figueroa J, Flanagan JL, Hayman MJ, Eisman JA, Kouzmenko AP. Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription. J Biol Chem. 2001 May 25;276(21):18243-8. Epub 2001 Mar 6. PMID:11278756 doi:http://dx.doi.org/10.1074/jbc.M010815200
- ↑ Kim YJ, Noguchi S, Hayashi YK, Tsukahara T, Shimizu T, Arahata K. The product of an oculopharyngeal muscular dystrophy gene, poly(A)-binding protein 2, interacts with SKIP and stimulates muscle-specific gene expression. Hum Mol Genet. 2001 May 15;10(11):1129-39. PMID:11371506
- ↑ Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, MacDonald PN. Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription. J Biol Chem. 2001 Nov 2;276(44):40614-20. Epub 2001 Aug 20. PMID:11514567 doi:http://dx.doi.org/10.1074/jbc.M106263200
- ↑ Zhang C, Dowd DR, Staal A, Gu C, Lian JB, van Wijnen AJ, Stein GS, MacDonald PN. Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing. J Biol Chem. 2003 Sep 12;278(37):35325-36. Epub 2003 Jul 2. PMID:12840015 doi:http://dx.doi.org/10.1074/jbc.M305191200
- ↑ Leong GM, Subramaniam N, Issa LL, Barry JB, Kino T, Driggers PH, Hayman MJ, Eisman JA, Gardiner EM. Ski-interacting protein, a bifunctional nuclear receptor coregulator that interacts with N-CoR/SMRT and p300. Biochem Biophys Res Commun. 2004 Mar 19;315(4):1070-6. PMID:14985122 doi:http://dx.doi.org/10.1016/j.bbrc.2004.02.004
- ↑ Figueroa JD, Hayman MJ. The human Ski-interacting protein functionally substitutes for the yeast PRP45 gene. Biochem Biophys Res Commun. 2004 Jul 9;319(4):1105-9. PMID:15194481 doi:http://dx.doi.org/10.1016/j.bbrc.2004.05.096
- ↑ Bres V, Gomes N, Pickle L, Jones KA. A human splicing factor, SKIP, associates with P-TEFb and enhances transcription elongation by HIV-1 Tat. Genes Dev. 2005 May 15;19(10):1211-26. PMID:15905409 doi:http://dx.doi.org/10.1101/gad.1291705
- ↑ Bracken CP, Wall SJ, Barre B, Panov KI, Ajuh PM, Perkins ND. Regulation of cyclin D1 RNA stability by SNIP1. Cancer Res. 2008 Sep 15;68(18):7621-8. doi: 10.1158/0008-5472.CAN-08-1217. PMID:18794151 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-1217
- ↑ Bres V, Yoshida T, Pickle L, Jones KA. SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation. Mol Cell. 2009 Oct 9;36(1):75-87. doi: 10.1016/j.molcel.2009.08.015. PMID:19818711 doi:http://dx.doi.org/10.1016/j.molcel.2009.08.015
- ↑ Vasquez-Del Carpio R, Kaplan FM, Weaver KL, VanWye JD, Alves-Guerra MC, Robbins DJ, Capobianco AJ. Assembly of a Notch transcriptional activation complex requires multimerization. Mol Cell Biol. 2011 Apr;31(7):1396-408. doi: 10.1128/MCB.00360-10. Epub 2011 Jan , 18. PMID:21245387 doi:http://dx.doi.org/10.1128/MCB.00360-10
- ↑ Chen Y, Zhang L, Jones KA. SKIP counteracts p53-mediated apoptosis via selective regulation of p21Cip1 mRNA splicing. Genes Dev. 2011 Apr 1;25(7):701-16. doi: 10.1101/gad.2002611. PMID:21460037 doi:http://dx.doi.org/10.1101/gad.2002611
- ↑ Baudino TA, Kraichely DM, Jefcoat SC Jr, Winchester SK, Partridge NC, MacDonald PN. Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription. J Biol Chem. 1998 Jun 26;273(26):16434-41. PMID:9632709
- ↑ Haselbach D, Komarov I, Agafonov DE, Hartmuth K, Graf B, Dybkov O, Urlaub H, Kastner B, Luhrmann R, Stark H. Structure and Conformational Dynamics of the Human Spliceosomal B(act) Complex. Cell. 2018 Jan 25;172(3):454-464.e11. doi: 10.1016/j.cell.2018.01.010. Epub 2018 , Jan 17. PMID:29361316 doi:http://dx.doi.org/10.1016/j.cell.2018.01.010
|
