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| | <SX load='5o9z' size='340' side='right' viewer='molstar' caption='[[5o9z]], [[Resolution|resolution]] 4.50Å' scene=''> | | <SX load='5o9z' size='340' side='right' viewer='molstar' caption='[[5o9z]], [[Resolution|resolution]] 4.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5o9z]] is a 57 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O9Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5O9Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5o9z]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O9Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5O9Z FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA_helicase RNA helicase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.13 3.6.4.13] </span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.5Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5o9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o9z OCA], [http://pdbe.org/5o9z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o9z RCSB], [http://www.ebi.ac.uk/pdbsum/5o9z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o9z ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5o9z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o9z OCA], [https://pdbe.org/5o9z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5o9z RCSB], [https://www.ebi.ac.uk/pdbsum/5o9z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5o9z ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PRP6_HUMAN 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. [[http://www.uniprot.org/uniprot/U5S1_HUMAN U5S1_HUMAN]] Mandibulofacial dysostosis-microcephaly syndrome. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/PRP8_HUMAN PRP8_HUMAN]] Defects in PRPF8 are the cause of retinitis pigmentosa type 13 (RP13) [MIM:[http://omim.org/entry/600059 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.<ref>PMID:17317632</ref> <ref>PMID:11468273</ref> [:]<ref>PMID:11910553</ref> <ref>PMID:12714658</ref> [[http://www.uniprot.org/uniprot/U520_HUMAN U520_HUMAN]] Retinitis pigmentosa. Retinitis pigmentosa 33 (RP33) [MIM:[http://omim.org/entry/610359 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.<ref>PMID:16723661</ref> <ref>PMID:23045696</ref> <ref>PMID:19878916</ref> <ref>PMID:19710410</ref> <ref>PMID:21618346</ref> [[http://www.uniprot.org/uniprot/PRP31_HUMAN PRP31_HUMAN]] Defects in PRPF31 are the cause of retinitis pigmentosa type 11 (RP11) [MIM:[http://omim.org/entry/600138 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.<ref>PMID:17412961</ref> <ref>PMID:12444105</ref> <ref>PMID:11545739</ref> <ref>PMID:8808602</ref> <ref>PMID:12923864</ref> [[http://www.uniprot.org/uniprot/PRPF3_HUMAN PRPF3_HUMAN]] Defects in PRPF3 are the cause of retinitis pigmentosa type 18 (RP18) [MIM:[http://omim.org/entry/601414 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.<ref>PMID:11773002</ref> <ref>PMID:12714658</ref> <ref>PMID:17932117</ref> | + | [https://www.uniprot.org/uniprot/PRP8_HUMAN PRP8_HUMAN] Defects in PRPF8 are the cause of retinitis pigmentosa type 13 (RP13) [MIM:[https://omim.org/entry/600059 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.<ref>PMID:17317632</ref> <ref>PMID:11468273</ref> [:]<ref>PMID:11910553</ref> <ref>PMID:12714658</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SF3B1_HUMAN 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. [[http://www.uniprot.org/uniprot/LSM8_HUMAN LSM8_HUMAN]] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [[http://www.uniprot.org/uniprot/RUXE_HUMAN 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. [[http://www.uniprot.org/uniprot/PRP6_HUMAN 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.<ref>PMID:12039962</ref> [[http://www.uniprot.org/uniprot/LSM2_HUMAN LSM2_HUMAN]] Binds specifically to the 3'-terminal U-tract of U6 snRNA. May be involved in pre-mRNA splicing. [[http://www.uniprot.org/uniprot/U5S1_HUMAN U5S1_HUMAN]] Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing. Binds GTP. [[http://www.uniprot.org/uniprot/WBP4_HUMAN 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.<ref>PMID:9724750</ref> <ref>PMID:19592703</ref> [[http://www.uniprot.org/uniprot/PRP8_HUMAN 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. [[http://www.uniprot.org/uniprot/RED_HUMAN RED_HUMAN]] May bind to chromatin. [[http://www.uniprot.org/uniprot/LSM6_HUMAN 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). [[http://www.uniprot.org/uniprot/SNUT1_HUMAN 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.<ref>PMID:11350945</ref> [[http://www.uniprot.org/uniprot/LSM3_HUMAN LSM3_HUMAN]] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [[http://www.uniprot.org/uniprot/SMD1_HUMAN SMD1_HUMAN]] May act as a charged protein scaffold to promote snRNP assembly or strengthen snRNP-snRNP interactions through nonspecific electrostatic contacts with RNA. [[http://www.uniprot.org/uniprot/LSM4_HUMAN LSM4_HUMAN]] Binds specifically to the 3'-terminal U-tract of U6 snRNA. [[http://www.uniprot.org/uniprot/RUXF_HUMAN 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. [[http://www.uniprot.org/uniprot/RSMB_HUMAN 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). [[http://www.uniprot.org/uniprot/TXN4A_HUMAN TXN4A_HUMAN]] Essential role in pre-mRNA splicing. [[http://www.uniprot.org/uniprot/LSM7_HUMAN LSM7_HUMAN]] Binds specifically to the 3'-terminal U-tract of U6 snRNA and is probably a component of the spliceosome. [[http://www.uniprot.org/uniprot/MFAP1_HUMAN MFAP1_HUMAN]] Component of the elastin-associated microfibrils. [[http://www.uniprot.org/uniprot/RUXG_HUMAN 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. [[http://www.uniprot.org/uniprot/PPIH_HUMAN 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.<ref>PMID:9570313</ref> <ref>PMID:11823439</ref> <ref>PMID:12875835</ref> [[http://www.uniprot.org/uniprot/SMD3_HUMAN 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.<ref>PMID:11574479</ref> [[http://www.uniprot.org/uniprot/LSM5_HUMAN 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. [[http://www.uniprot.org/uniprot/PRP4_HUMAN PRP4_HUMAN]] Involved in pre-mRNA splicing. [[http://www.uniprot.org/uniprot/U520_HUMAN 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.<ref>PMID:16723661</ref> <ref>PMID:8670905</ref> <ref>PMID:9539711</ref> <ref>PMID:23045696</ref> [[http://www.uniprot.org/uniprot/PHF5A_HUMAN 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.<ref>PMID:12234937</ref> [[http://www.uniprot.org/uniprot/PR38A_HUMAN PR38A_HUMAN]] May be required for pre-mRNA splicing. [[http://www.uniprot.org/uniprot/NH2L1_HUMAN 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.<ref>PMID:10545122</ref> <ref>PMID:17412961</ref> [[http://www.uniprot.org/uniprot/PRP31_HUMAN PRP31_HUMAN]] Involved in pre-mRNA splicing. Required for U4/U6.U5 tri-snRNP formation.<ref>PMID:11867543</ref> [[http://www.uniprot.org/uniprot/RU2B_HUMAN 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. [[http://www.uniprot.org/uniprot/SNR40_HUMAN 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.<ref>PMID:9774689</ref> [[http://www.uniprot.org/uniprot/SF3B3_HUMAN 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. [[http://www.uniprot.org/uniprot/RU2A_HUMAN RU2A_HUMAN]] This protein is associated with sn-RNP U2. It helps the A' protein to bind stem loop IV of U2 snRNA. [[http://www.uniprot.org/uniprot/SMD2_HUMAN SMD2_HUMAN]] Required for pre-mRNA splicing. Required for snRNP biogenesis (By similarity). [[http://www.uniprot.org/uniprot/PRPF3_HUMAN PRPF3_HUMAN]] Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex. | + | [https://www.uniprot.org/uniprot/PRP8_HUMAN 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 22: |
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| | | | |
| | ==See Also== | | ==See Also== |
| | + | *[[Nucleoprotein 3D structures|Nucleoprotein 3D structures]] |
| | *[[Pre-mRNA splicing factors 3D structures|Pre-mRNA splicing factors 3D structures]] | | *[[Pre-mRNA splicing factors 3D structures|Pre-mRNA splicing factors 3D structures]] |
| | + | *[[Sm-like protein 3D structures|Sm-like protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 29: |
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| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: RNA helicase]]
| + | [[Category: Bertram K]] |
| - | [[Category: Bertram, K]] | + | [[Category: Kastner B]] |
| - | [[Category: Kastner, B]] | + | |
| - | [[Category: Macromolecular complex]]
| + | |
| - | [[Category: Pre-mrna splicing]]
| + | |
| - | [[Category: Spliceosome]]
| + | |
| - | [[Category: Splicing]]
| + | |
| Structural highlights
Disease
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
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.
Publication Abstract from PubMed
Little is known about the spliceosome's structure before its extensive remodeling into a catalytically active complex. Here, we report a 3D cryo-EM structure of a pre-catalytic human spliceosomal B complex. The U2 snRNP-containing head domain is connected to the B complex main body via three main bridges. U4/U6.U5 tri-snRNP proteins, which are located in the main body, undergo significant rearrangements during tri-snRNP integration into the B complex. These include formation of a partially closed Prp8 conformation that creates, together with Dim1, a 5' splice site (ss) binding pocket, displacement of Sad1, and rearrangement of Brr2 such that it contacts its U4/U6 substrate and is poised for the subsequent spliceosome activation step. The molecular organization of several B-specific proteins suggests that they are involved in negatively regulating Brr2, positioning the U6/5'ss helix, and stabilizing the B complex structure. Our results indicate significant differences between the early activation phase of human and yeast spliceosomes.
Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for Activation.,Bertram K, Agafonov DE, Dybkov O, Haselbach D, Leelaram MN, Will CL, Urlaub H, Kastner B, Luhrmann R, Stark H Cell. 2017 Aug 10;170(4):701-713.e11. doi: 10.1016/j.cell.2017.07.011. Epub 2017 , Aug 3. PMID:28781166[5]
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
- ↑ Bertram K, Agafonov DE, Dybkov O, Haselbach D, Leelaram MN, Will CL, Urlaub H, Kastner B, Luhrmann R, Stark H. Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for Activation. Cell. 2017 Aug 10;170(4):701-713.e11. doi: 10.1016/j.cell.2017.07.011. Epub 2017 , Aug 3. PMID:28781166 doi:http://dx.doi.org/10.1016/j.cell.2017.07.011
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