| Structural highlights
Function
TRBP2_HUMAN Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1. Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs. This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha. May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
The accurate cleavage of pre-micro(mi)RNAs by Dicer and mi/siRNA guide strand selection are important steps in forming the RNA-induced silencing complex (RISC). The role of Dicer binding partner TRBP in these processes remains poorly understood. Here, we solved the solution structure of the two N-terminal dsRNA binding domains (dsRBDs) of TRBP in complex with a functionally asymmetric siRNA using NMR, EPR, and single-molecule spectroscopy. We find that siRNA recognition by the dsRBDs is not sequence-specific but rather depends on the RNA shape. The two dsRBDs can swap their binding sites, giving rise to two equally populated, pseudo-symmetrical complexes, showing that TRBP is not a primary sensor of siRNA asymmetry. Using our structure to model a Dicer-TRBP-siRNA ternary complex, we show that TRBP's dsRBDs and Dicer's RNase III domains bind a canonical 19 base pair siRNA on opposite sides, supporting a mechanism whereby TRBP influences Dicer-mediated cleavage accuracy by binding the dsRNA region of the pre-miRNA during Dicer cleavage.
Structural basis of siRNA recognition by TRBP double-stranded RNA binding domains.,Masliah G, Maris C, Konig SL, Yulikov M, Aeschimann F, Malinowska AL, Mabille J, Weiler J, Holla A, Hunziker J, Meisner-Kober N, Schuler B, Jeschke G, Allain FH EMBO J. 2018 Feb 15. pii: embj.201797089. doi: 10.15252/embj.201797089. PMID:29449323[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dorin D, Bonnet MC, Bannwarth S, Gatignol A, Meurs EF, Vaquero C. The TAR RNA-binding protein, TRBP, stimulates the expression of TAR-containing RNAs in vitro and in vivo independently of its ability to inhibit the dsRNA-dependent kinase PKR. J Biol Chem. 2003 Feb 14;278(7):4440-8. Epub 2002 Dec 9. PMID:12475984 doi:10.1074/jbc.M208954200
- ↑ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005 Nov 18;123(4):631-40. Epub 2005 Nov 3. PMID:16271387 doi:10.1016/j.cell.2005.10.022
- ↑ Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005 Oct;6(10):961-7. PMID:16142218 doi:10.1038/sj.embor.7400509
- ↑ Maniataki E, Mourelatos Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005 Dec 15;19(24):2979-90. PMID:16357216 doi:10.1101/gad.1384005
- ↑ Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005 Aug 4;436(7051):740-4. Epub 2005 Jun 22. PMID:15973356 doi:10.1038/nature03868
- ↑ Lee Y, Hur I, Park SY, Kim YK, Suh MR, Kim VN. The role of PACT in the RNA silencing pathway. EMBO J. 2006 Feb 8;25(3):522-32. Epub 2006 Jan 19. PMID:16424907 doi:10.1038/sj.emboj.7600942
- ↑ Kok KH, Ng MH, Ching YP, Jin DY. Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. J Biol Chem. 2007 Jun 15;282(24):17649-57. Epub 2007 Apr 23. PMID:17452327 doi:10.1074/jbc.M611768200
- ↑ MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):512-7. doi: 10.1073/pnas.0710869105., Epub 2008 Jan 4. PMID:18178619 doi:10.1073/pnas.0710869105
- ↑ Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, Rossi S, Fernandez AF, Carneiro F, Oliveira C, Ferreira B, Liu CG, Villanueva A, Capella G, Schwartz S Jr, Shiekhattar R, Esteller M. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet. 2009 Mar;41(3):365-70. doi: 10.1038/ng.317. Epub 2009 Feb 15. PMID:19219043 doi:10.1038/ng.317
- ↑ Masliah G, Maris C, Konig SL, Yulikov M, Aeschimann F, Malinowska AL, Mabille J, Weiler J, Holla A, Hunziker J, Meisner-Kober N, Schuler B, Jeschke G, Allain FH. Structural basis of siRNA recognition by TRBP double-stranded RNA binding domains. EMBO J. 2018 Feb 15. pii: embj.201797089. doi: 10.15252/embj.201797089. PMID:29449323 doi:https://dx.doi.org/10.15252/embj.201797089
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