Mechanism of 5' splice site transfer for human spliceosome activation
The prespliceosome, comprising U1 and U2 small nuclear ribonucleoproteins (snRNPs) bound to the precursor messenger RNA 5' splice site (5'SS) and branch point sequence, associates with the U4/U6.U5 tri-snRNP to form the fully assembled precatalytic pre-B spliceosome. Here, we report cryo-e...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2019-04, Vol.364 (6438), p.362-367 |
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| creator | Charenton, Clément Wilkinson, Max E Nagai, Kiyoshi |
| description | The prespliceosome, comprising U1 and U2 small nuclear ribonucleoproteins (snRNPs) bound to the precursor messenger RNA 5' splice site (5'SS) and branch point sequence, associates with the U4/U6.U5 tri-snRNP to form the fully assembled precatalytic pre-B spliceosome. Here, we report cryo-electron microscopy structures of the human pre-B complex captured before U1 snRNP dissociation at 3.3-angstrom core resolution and the human tri-snRNP at 2.9-angstrom resolution. U1 snRNP inserts the 5'SS-U1 snRNA helix between the two RecA domains of the Prp28 DEAD-box helicase. Adenosine 5'-triphosphate-dependent closure of the Prp28 RecA domains releases the 5'SS to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggest that formation of the 5'SS-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome. |
| doi_str_mv | 10.1126/science.aax3289 |
| format | Article |
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Here, we report cryo-electron microscopy structures of the human pre-B complex captured before U1 snRNP dissociation at 3.3-angstrom core resolution and the human tri-snRNP at 2.9-angstrom resolution. U1 snRNP inserts the 5'SS-U1 snRNA helix between the two RecA domains of the Prp28 DEAD-box helicase. Adenosine 5'-triphosphate-dependent closure of the Prp28 RecA domains releases the 5'SS to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggest that formation of the 5'SS-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aax3289</identifier><identifier>PMID: 30975767</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>ATP ; Catalysis ; Cryoelectron Microscopy ; DNA helicase ; Domains ; Electron microscopy ; Humans ; Inserts ; mRNA ; Nucleotide sequence ; Precursors ; Protein Conformation ; Proteins ; RecA protein ; Relocation ; Ribonucleic acid ; Ribonucleoprotein, U1 Small Nuclear - chemistry ; Ribonucleoprotein, U1 Small Nuclear - metabolism ; Ribonucleoprotein, U4-U6 Small Nuclear - chemistry ; Ribonucleoprotein, U4-U6 Small Nuclear - metabolism ; Ribonucleoproteins ; Ribonucleoproteins (small nuclear) ; Ribonucleoproteins, Small Nuclear - chemistry ; Ribonucleoproteins, Small Nuclear - metabolism ; RNA ; RNA Folding ; RNA Splice Sites ; RNA Splicing ; RNA, Small Nuclear - chemistry ; RNA, Small Nuclear - metabolism ; snRNA ; Spliceosomes - chemistry ; Spliceosomes - metabolism ; Spliceosomes - ultrastructure ; Splicing ; Unwinding</subject><ispartof>Science (American Association for the Advancement of Science), 2019-04, Vol.364 (6438), p.362-367</ispartof><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Here, we report cryo-electron microscopy structures of the human pre-B complex captured before U1 snRNP dissociation at 3.3-angstrom core resolution and the human tri-snRNP at 2.9-angstrom resolution. U1 snRNP inserts the 5'SS-U1 snRNA helix between the two RecA domains of the Prp28 DEAD-box helicase. Adenosine 5'-triphosphate-dependent closure of the Prp28 RecA domains releases the 5'SS to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggest that formation of the 5'SS-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome.</description><subject>ATP</subject><subject>Catalysis</subject><subject>Cryoelectron Microscopy</subject><subject>DNA helicase</subject><subject>Domains</subject><subject>Electron microscopy</subject><subject>Humans</subject><subject>Inserts</subject><subject>mRNA</subject><subject>Nucleotide sequence</subject><subject>Precursors</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>RecA protein</subject><subject>Relocation</subject><subject>Ribonucleic acid</subject><subject>Ribonucleoprotein, U1 Small Nuclear - chemistry</subject><subject>Ribonucleoprotein, U1 Small Nuclear - metabolism</subject><subject>Ribonucleoprotein, U4-U6 Small Nuclear - chemistry</subject><subject>Ribonucleoprotein, U4-U6 Small Nuclear - metabolism</subject><subject>Ribonucleoproteins</subject><subject>Ribonucleoproteins (small nuclear)</subject><subject>Ribonucleoproteins, Small Nuclear - chemistry</subject><subject>Ribonucleoproteins, Small Nuclear - metabolism</subject><subject>RNA</subject><subject>RNA Folding</subject><subject>RNA Splice Sites</subject><subject>RNA Splicing</subject><subject>RNA, Small Nuclear - chemistry</subject><subject>RNA, Small Nuclear - metabolism</subject><subject>snRNA</subject><subject>Spliceosomes - chemistry</subject><subject>Spliceosomes - metabolism</subject><subject>Spliceosomes - ultrastructure</subject><subject>Splicing</subject><subject>Unwinding</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkTtPwzAUhS0EoqUws6FIDLAE_EzsBQlV5SGBWGC2jGNTV4ld7KSCf08iQgVMdzifz73HB4BjBC8QwsVl0s54bS6U-iCYix0wRVCwXGBIdsEUQlLkHJZsAg5SWkHYa4LsgwmBomRlUU7B4tHopfIuNVmwGTvL0rp22mTJtSZro_LJmpjZELNl1yg_yiGFxmRKt26jWhf8Idizqk7maJwz8HKzeJ7f5Q9Pt_fz64dcU8bbnKLCWqg0wRUnlFdKETPEYK-VoKyilpUaUtJDmiOCKMNKKFgYjRHHyAoyA1ffvuvutTGVNr4_sZbr6BoVP2VQTv5VvFvKt7CRBcMMCt4bnI8GMbx3JrWycUmbulbehC5JjIcvKikedp3-Q1ehi76P11OIQcQ4pj11-U3pGFKKxm6PQVAO2eRYkRwr6l-c_M6w5X86IV_b4o8u</recordid><startdate>20190426</startdate><enddate>20190426</enddate><creator>Charenton, Clément</creator><creator>Wilkinson, Max E</creator><creator>Nagai, Kiyoshi</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8959-7012</orcidid><orcidid>https://orcid.org/0000-0003-4738-9503</orcidid><orcidid>https://orcid.org/0000-0003-1785-6510</orcidid></search><sort><creationdate>20190426</creationdate><title>Mechanism of 5' splice site transfer for human spliceosome activation</title><author>Charenton, Clément ; Wilkinson, Max E ; Nagai, Kiyoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c458t-416ff0ac32d8348daa3e11265bd945d4f57c0436ffc8131452a9a06ec21821f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>ATP</topic><topic>Catalysis</topic><topic>Cryoelectron Microscopy</topic><topic>DNA helicase</topic><topic>Domains</topic><topic>Electron microscopy</topic><topic>Humans</topic><topic>Inserts</topic><topic>mRNA</topic><topic>Nucleotide sequence</topic><topic>Precursors</topic><topic>Protein Conformation</topic><topic>Proteins</topic><topic>RecA protein</topic><topic>Relocation</topic><topic>Ribonucleic acid</topic><topic>Ribonucleoprotein, U1 Small Nuclear - chemistry</topic><topic>Ribonucleoprotein, U1 Small Nuclear - metabolism</topic><topic>Ribonucleoprotein, U4-U6 Small Nuclear - chemistry</topic><topic>Ribonucleoprotein, U4-U6 Small Nuclear - metabolism</topic><topic>Ribonucleoproteins</topic><topic>Ribonucleoproteins (small nuclear)</topic><topic>Ribonucleoproteins, Small Nuclear - chemistry</topic><topic>Ribonucleoproteins, Small Nuclear - metabolism</topic><topic>RNA</topic><topic>RNA Folding</topic><topic>RNA Splice Sites</topic><topic>RNA Splicing</topic><topic>RNA, Small Nuclear - chemistry</topic><topic>RNA, Small Nuclear - metabolism</topic><topic>snRNA</topic><topic>Spliceosomes - chemistry</topic><topic>Spliceosomes - metabolism</topic><topic>Spliceosomes - ultrastructure</topic><topic>Splicing</topic><topic>Unwinding</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Charenton, Clément</creatorcontrib><creatorcontrib>Wilkinson, Max E</creatorcontrib><creatorcontrib>Nagai, Kiyoshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Charenton, Clément</au><au>Wilkinson, Max E</au><au>Nagai, Kiyoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of 5' splice site transfer for human spliceosome activation</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2019-04-26</date><risdate>2019</risdate><volume>364</volume><issue>6438</issue><spage>362</spage><epage>367</epage><pages>362-367</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>The prespliceosome, comprising U1 and U2 small nuclear ribonucleoproteins (snRNPs) bound to the precursor messenger RNA 5' splice site (5'SS) and branch point sequence, associates with the U4/U6.U5 tri-snRNP to form the fully assembled precatalytic pre-B spliceosome. Here, we report cryo-electron microscopy structures of the human pre-B complex captured before U1 snRNP dissociation at 3.3-angstrom core resolution and the human tri-snRNP at 2.9-angstrom resolution. U1 snRNP inserts the 5'SS-U1 snRNA helix between the two RecA domains of the Prp28 DEAD-box helicase. Adenosine 5'-triphosphate-dependent closure of the Prp28 RecA domains releases the 5'SS to pair with the nearby U6 ACAGAGA-box sequence presented as a mobile loop. The structures suggest that formation of the 5'SS-ACAGAGA helix triggers remodeling of an intricate protein-RNA network to induce Brr2 helicase relocation to its loading sequence in U4 snRNA, enabling Brr2 to unwind the U4/U6 snRNA duplex to allow U6 snRNA to form the catalytic center of the spliceosome.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>30975767</pmid><doi>10.1126/science.aax3289</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-8959-7012</orcidid><orcidid>https://orcid.org/0000-0003-4738-9503</orcidid><orcidid>https://orcid.org/0000-0003-1785-6510</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for the Advancement of Science |
| subjects | ATP Catalysis Cryoelectron Microscopy DNA helicase Domains Electron microscopy Humans Inserts mRNA Nucleotide sequence Precursors Protein Conformation Proteins RecA protein Relocation Ribonucleic acid Ribonucleoprotein, U1 Small Nuclear - chemistry Ribonucleoprotein, U1 Small Nuclear - metabolism Ribonucleoprotein, U4-U6 Small Nuclear - chemistry Ribonucleoprotein, U4-U6 Small Nuclear - metabolism Ribonucleoproteins Ribonucleoproteins (small nuclear) Ribonucleoproteins, Small Nuclear - chemistry Ribonucleoproteins, Small Nuclear - metabolism RNA RNA Folding RNA Splice Sites RNA Splicing RNA, Small Nuclear - chemistry RNA, Small Nuclear - metabolism snRNA Spliceosomes - chemistry Spliceosomes - metabolism Spliceosomes - ultrastructure Splicing Unwinding |
| title | Mechanism of 5' splice site transfer for human spliceosome activation |
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