6v4x | pdb_00006v4x

Cryo-EM structure of an active human histone pre-mRNA 3'-end processing machinery at 3.2 Angstrom resolution

Structural highlights

6v4x is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[LSM10_HUMAN] Appears to function in the U7 snRNP complex that is involved in histone 3'-end processing. Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed. Required for cell cycle progression from G1 to S phases. Binds specifically to U7 snRNA. Binds to the downstream cleavage product (DCP) of histone pre-mRNA in a U7 snRNP dependent manner.^[1] [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. [LSM11_HUMAN] Component of the U7 snRNP complex that is involved in the histone 3'-end pre-mRNA processing (By similarity). Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed. Required for cell cycle progression from G1 to S phases. Binds specifically to the Sm-binding site of U7 snRNA.^[2] [CPSF2_HUMAN] Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Involved in the histone 3' end pre-mRNA processing.^[3] ^[4] [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). [CPSF3_HUMAN] Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease. Also involved in the histone 3'-end pre-mRNA processing. U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner.^[5] ^[6] ^[7] ^[8] [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.^[9] [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. [SYMPK_HUMAN] Scaffold protein that functions as a component of a multimolecular complex involved in histone mRNA 3'-end processing. Specific component of the tight junction (TJ) plaque, but might not be an exclusively junctional component. May have a house-keeping rule. Is involved in pre-mRNA polyadenylation. Enhances SSU72 phosphatase activity.^[10] ^[11] [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.

Publication Abstract from PubMed

The 3'-end processing machinery for metazoan replication-dependent histone precursor messenger RNAs (pre-mRNAs) contains the U7 small nuclear ribonucleoprotein and shares the key cleavage module with the canonical cleavage and polyadenylation machinery. We reconstituted an active human histone pre-mRNA processing machinery using 13 recombinant proteins and two RNAs and determined its structure by cryo-electron microscopy. The overall structure is highly asymmetrical and resembles an amphora with one long handle. We captured the pre-mRNA in the active site of the endonuclease, the 73-kilodalton subunit of the cleavage and polyadenylation specificity factor, poised for cleavage. The endonuclease and the entire cleavage module undergo extensive rearrangements for activation, triggered through the recognition of the duplex between the authentic pre-mRNA and U7 small nuclear RNA (snRNA). Our study also has notable implications for understanding canonical and snRNA 3'-end processing.

Structure of an active human histone pre-mRNA 3'-end processing machinery.,Sun Y, Zhang Y, Aik WS, Yang XC, Marzluff WF, Walz T, Dominski Z, Tong L Science. 2020 Feb 7;367(6478):700-703. doi: 10.1126/science.aaz7758. PMID:32029631^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wagner EJ, Marzluff WF. ZFP100, a component of the active U7 snRNP limiting for histone pre-mRNA processing, is required for entry into S phase. Mol Cell Biol. 2006 Sep;26(17):6702-12. PMID:16914750 doi:https://dx.doi.org/26/17/6702
↑ Wagner EJ, Marzluff WF. ZFP100, a component of the active U7 snRNP limiting for histone pre-mRNA processing, is required for entry into S phase. Mol Cell Biol. 2006 Sep;26(17):6702-12. PMID:16914750 doi:https://dx.doi.org/26/17/6702
↑ Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:https://dx.doi.org/10.1038/sj.emboj.7600070
↑ Kolev NG, Yario TA, Benson E, Steitz JA. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation. EMBO Rep. 2008 Oct;9(10):1013-8. doi: 10.1038/embor.2008.146. Epub 2008 Aug 8. PMID:18688255 doi:https://dx.doi.org/10.1038/embor.2008.146
↑ Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:https://dx.doi.org/10.1038/sj.emboj.7600070
↑ Ryan K, Calvo O, Manley JL. Evidence that polyadenylation factor CPSF-73 is the mRNA 3' processing endonuclease. RNA. 2004 Apr;10(4):565-73. PMID:15037765
↑ Kolev NG, Yario TA, Benson E, Steitz JA. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation. EMBO Rep. 2008 Oct;9(10):1013-8. doi: 10.1038/embor.2008.146. Epub 2008 Aug 8. PMID:18688255 doi:https://dx.doi.org/10.1038/embor.2008.146
↑ Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V, Manley JL, Tong L. Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease. Nature. 2006 Dec 14;444(7121):953-6. Epub 2006 Nov 26. PMID:17128255 doi:10.1038/nature05363
↑ 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
↑ Kolev NG, Steitz JA. Symplekin and multiple other polyadenylation factors participate in 3'-end maturation of histone mRNAs. Genes Dev. 2005 Nov 1;19(21):2583-92. Epub 2005 Oct 17. PMID:16230528 doi:10.1101/gad.1371105
↑ Xiang K, Nagaike T, Xiang S, Kilic T, Beh MM, Manley JL, Tong L. Crystal structure of the human symplekin-Ssu72-CTD phosphopeptide complex. Nature. 2010 Sep 22. PMID:20861839 doi:10.1038/nature09391
↑ Sun Y, Zhang Y, Aik WS, Yang XC, Marzluff WF, Walz T, Dominski Z, Tong L. Structure of an active human histone pre-mRNA 3'-end processing machinery. Science. 2020 Feb 7;367(6478):700-703. doi: 10.1126/science.aaz7758. PMID:32029631 doi:https://dx.doi.org/10.1126/science.aaz7758

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[1] Wagner EJ, Marzluff WF. ZFP100, a component of the active U7 snRNP limiting for histone pre-mRNA processing, is required for entry into S phase. Mol Cell Biol. 2006 Sep;26(17):6702-12. PMID:16914750 doi:https://dx.doi.org/26/17/6702

[2] Wagner EJ, Marzluff WF. ZFP100, a component of the active U7 snRNP limiting for histone pre-mRNA processing, is required for entry into S phase. Mol Cell Biol. 2006 Sep;26(17):6702-12. PMID:16914750 doi:https://dx.doi.org/26/17/6702

[3] Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:https://dx.doi.org/10.1038/sj.emboj.7600070

[4] Kolev NG, Yario TA, Benson E, Steitz JA. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation. EMBO Rep. 2008 Oct;9(10):1013-8. doi: 10.1038/embor.2008.146. Epub 2008 Aug 8. PMID:18688255 doi:https://dx.doi.org/10.1038/embor.2008.146

[5] Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:https://dx.doi.org/10.1038/sj.emboj.7600070

[6] Ryan K, Calvo O, Manley JL. Evidence that polyadenylation factor CPSF-73 is the mRNA 3' processing endonuclease. RNA. 2004 Apr;10(4):565-73. PMID:15037765

[7] Kolev NG, Yario TA, Benson E, Steitz JA. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation. EMBO Rep. 2008 Oct;9(10):1013-8. doi: 10.1038/embor.2008.146. Epub 2008 Aug 8. PMID:18688255 doi:https://dx.doi.org/10.1038/embor.2008.146

[8] Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V, Manley JL, Tong L. Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease. Nature. 2006 Dec 14;444(7121):953-6. Epub 2006 Nov 26. PMID:17128255 doi:10.1038/nature05363

[9] 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

[10] Kolev NG, Steitz JA. Symplekin and multiple other polyadenylation factors participate in 3'-end maturation of histone mRNAs. Genes Dev. 2005 Nov 1;19(21):2583-92. Epub 2005 Oct 17. PMID:16230528 doi:10.1101/gad.1371105

[11] Xiang K, Nagaike T, Xiang S, Kilic T, Beh MM, Manley JL, Tong L. Crystal structure of the human symplekin-Ssu72-CTD phosphopeptide complex. Nature. 2010 Sep 22. PMID:20861839 doi:10.1038/nature09391

[12] Sun Y, Zhang Y, Aik WS, Yang XC, Marzluff WF, Walz T, Dominski Z, Tong L. Structure of an active human histone pre-mRNA 3'-end processing machinery. Science. 2020 Feb 7;367(6478):700-703. doi: 10.1126/science.aaz7758. PMID:32029631 doi:https://dx.doi.org/10.1126/science.aaz7758

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6v4x | pdb_00006v4x

Cryo-EM structure of an active human histone pre-mRNA 3'-end processing machinery at 3.2 Angstrom resolution

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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