| Structural highlights
Function
[NCBP1_HUMAN] Component of the cap-binding complex (CBC), which binds cotranscriptionally to the 5'-cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5'-end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2 and is required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP1/CBP80 does not bind directly capped RNAs (m7GpppG-capped RNA) but is required to stabilize the movement of the N-terminal loop of NCBP2/CBP20 and lock the CBC into a high affinity cap-binding state with the cap structure.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [NCBP2_HUMAN] Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure.[13] [14] [15] [16] [17] [18] [19]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The heterodimeric nuclear cap binding complex (CBC) binds to 5'-capped polymerase II transcripts. It enhances the efficiency of several mRNA maturation steps and is essential for U snRNA nuclear export in multicellular eukaryotes. The 2A crystal structure of human CBC shows that the large subunit, CBP80, comprises three domains, each containing consecutive helical hairpins and resembling the so-called MIF4G domain found in several other proteins involved in RNA metabolism. The small subunit, CPB20, has an RNP fold and associates with the second and third domains of CBP80. Site-directed mutagenesis revealed 4 residues of CBP20 which are critical for cap binding. A model for cap binding is proposed based on these results and the known mode of binding of RNA to RNP domains.
Crystal structure of the human nuclear cap binding complex.,Mazza C, Ohno M, Segref A, Mattaj IW, Cusack S Mol Cell. 2001 Aug;8(2):383-96. PMID:11545740[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Izaurralde E, Lewis J, McGuigan C, Jankowska M, Darzynkiewicz E, Mattaj IW. A nuclear cap binding protein complex involved in pre-mRNA splicing. Cell. 1994 Aug 26;78(4):657-68. PMID:8069914
- ↑ Izaurralde E, Lewis J, Gamberi C, Jarmolowski A, McGuigan C, Mattaj IW. A cap-binding protein complex mediating U snRNA export. Nature. 1995 Aug 24;376(6542):709-12. PMID:7651522 doi:http://dx.doi.org/10.1038/376709a0
- ↑ Ishigaki Y, Li X, Serin G, Maquat LE. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell. 2001 Sep 7;106(5):607-17. PMID:11551508
- ↑ Chiu SY, Lejeune F, Ranganathan AC, Maquat LE. The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Genes Dev. 2004 Apr 1;18(7):745-54. Epub 2004 Apr 1. PMID:15059963 doi:http://dx.doi.org/10.1101/gad.1170204
- ↑ Lejeune F, Ranganathan AC, Maquat LE. eIF4G is required for the pioneer round of translation in mammalian cells. Nat Struct Mol Biol. 2004 Oct;11(10):992-1000. Epub 2004 Sep 7. PMID:15361857 doi:http://dx.doi.org/10.1038/nsmb824
- ↑ Hosoda N, Kim YK, Lejeune F, Maquat LE. CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells. Nat Struct Mol Biol. 2005 Oct;12(10):893-901. Epub 2005 Sep 25. PMID:16186820 doi:http://dx.doi.org/10.1038/nsmb995
- ↑ Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R. Human mRNA export machinery recruited to the 5' end of mRNA. Cell. 2006 Dec 29;127(7):1389-400. PMID:17190602 doi:http://dx.doi.org/10.1016/j.cell.2006.10.044
- ↑ Balatsos NA, Nilsson P, Mazza C, Cusack S, Virtanen A. Inhibition of mRNA deadenylation by the nuclear cap binding complex (CBC). J Biol Chem. 2006 Feb 17;281(7):4517-22. Epub 2005 Nov 28. PMID:16317009 doi:http://dx.doi.org/10.1074/jbc.M508590200
- ↑ Matsuda D, Hosoda N, Kim YK, Maquat LE. Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nat Struct Mol Biol. 2007 Oct;14(10):974-9. Epub 2007 Sep 16. PMID:17873884 doi:http://dx.doi.org/10.1038/nsmb1297
- ↑ Woeller CF, Gaspari M, Isken O, Maquat LE. NMD resulting from encephalomyocarditis virus IRES-directed translation initiation seems to be restricted to CBP80/20-bound mRNA. EMBO Rep. 2008 May;9(5):446-51. doi: 10.1038/embor.2008.36. Epub 2008 Mar 28. PMID:18369367 doi:http://dx.doi.org/10.1038/embor.2008.36
- ↑ Gruber JJ, Zatechka DS, Sabin LR, Yong J, Lum JJ, Kong M, Zong WX, Zhang Z, Lau CK, Rawlings J, Cherry S, Ihle JN, Dreyfuss G, Thompson CB. Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation. Cell. 2009 Jul 23;138(2):328-39. doi: 10.1016/j.cell.2009.04.046. PMID:19632182 doi:http://dx.doi.org/10.1016/j.cell.2009.04.046
- ↑ Kim KM, Cho H, Choi K, Kim J, Kim BW, Ko YG, Jang SK, Kim YK. A new MIF4G domain-containing protein, CTIF, directs nuclear cap-binding protein CBP80/20-dependent translation. Genes Dev. 2009 Sep 1;23(17):2033-45. doi: 10.1101/gad.1823409. Epub 2009 Jul 31. PMID:19648179 doi:http://dx.doi.org/10.1101/gad.1823409
- ↑ Ishigaki Y, Li X, Serin G, Maquat LE. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell. 2001 Sep 7;106(5):607-17. PMID:11551508
- ↑ Lejeune F, Ranganathan AC, Maquat LE. eIF4G is required for the pioneer round of translation in mammalian cells. Nat Struct Mol Biol. 2004 Oct;11(10):992-1000. Epub 2004 Sep 7. PMID:15361857 doi:http://dx.doi.org/10.1038/nsmb824
- ↑ Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R. Human mRNA export machinery recruited to the 5' end of mRNA. Cell. 2006 Dec 29;127(7):1389-400. PMID:17190602 doi:http://dx.doi.org/10.1016/j.cell.2006.10.044
- ↑ Nojima T, Hirose T, Kimura H, Hagiwara M. The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export. J Biol Chem. 2007 May 25;282(21):15645-51. Epub 2007 Mar 15. PMID:17363367 doi:http://dx.doi.org/10.1074/jbc.M700629200
- ↑ Matsuda D, Hosoda N, Kim YK, Maquat LE. Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nat Struct Mol Biol. 2007 Oct;14(10):974-9. Epub 2007 Sep 16. PMID:17873884 doi:http://dx.doi.org/10.1038/nsmb1297
- ↑ Woeller CF, Gaspari M, Isken O, Maquat LE. NMD resulting from encephalomyocarditis virus IRES-directed translation initiation seems to be restricted to CBP80/20-bound mRNA. EMBO Rep. 2008 May;9(5):446-51. doi: 10.1038/embor.2008.36. Epub 2008 Mar 28. PMID:18369367 doi:http://dx.doi.org/10.1038/embor.2008.36
- ↑ Gruber JJ, Zatechka DS, Sabin LR, Yong J, Lum JJ, Kong M, Zong WX, Zhang Z, Lau CK, Rawlings J, Cherry S, Ihle JN, Dreyfuss G, Thompson CB. Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation. Cell. 2009 Jul 23;138(2):328-39. doi: 10.1016/j.cell.2009.04.046. PMID:19632182 doi:http://dx.doi.org/10.1016/j.cell.2009.04.046
- ↑ Mazza C, Ohno M, Segref A, Mattaj IW, Cusack S. Crystal structure of the human nuclear cap binding complex. Mol Cell. 2001 Aug;8(2):383-96. PMID:11545740
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