| Structural highlights
Function
[DDX3X_HUMAN] Multifunctional ATP-dependent RNA helicase. The ATPase activity can be stimulated by various ribo- and deoxynucleic acids indicative for a relaxed substrate specificity. In vitro can unwind partially double stranded DNA with a preference for 5'-single stranded DNA overhangs. Is involved in several steps of gene expression, such as transcription, mRNA maturation, mRNA export and translation. However, the exact mechanisms are not known and some functions may be specific for a subset of mRNAs. Involved in transcriptional regulation. Can enhance transcription from the CDKN1A/WAF1 promoter in a SP1-dependent manner. Found associated with the E-cadherin promoter and can down-regulate transcription from the promoter. Involved in regulation of translation initiation. Proposed to be involved in positive regulation of translation such as of cyclin E1/CCNE1 mRNA and specifically of mRNAs containing complex secondary structures in their 5'UTRs; these functions seem to require RNA helicase activity. Specifically promotes translation of a subset of viral and cellular mRNAs carrying a 5'proximal stem-loop structure in their 5'UTRs and cooperates with the eIF4F complex. Proposed to act prior to 43S ribosomal scanning and to locally destabilize these RNA structures to allow recognition of the mRNA cap or loading onto the 40S subunit. After association with 40S ribosomal subunits seems to be involved in the functional assembly of 80S ribosomes; the function seems to cover translation of mRNAs with structured and non-structured 5'UTRs and is independent of RNA helicase activity. Also proposed to inhibit cap-dependent translation by competetive interaction with EIF4E which can block the EIF4E:EIF4G complex formation. Proposed to be involved in stress response and stress granule assembly; the function is independent of RNA helicase activity and seems to involve association with EIF4E. May be involved in nuclear export of specific mRNAs but not in bulk mRNA export via interactions with XPO1 and NXF1. Also associates with polyadenylated mRNAs independently of NXF1. Associates with spliced mRNAs in an exon junction complex (EJC)-dependent manner and seems not to be directly involved in splicing. May be involved in nuclear mRNA export by association with DDX5 and regulating its nuclear location. Involved in innate immune signaling promoting the production of type I interferon (IFN-alpha and IFN-beta); proposed to act as viral RNA sensor, signaling intermediate and transcriptional coactivator. Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFN-beta induction. Also found associated with IFN-beta promoters; the function is independent of IRF3. Can bind to viral RNAs and via association with MAVS/IPS1 and DDX58/RIG-I is thought to induce signaling in early stages of infection. Involved in regulation of apoptosis. May be required for activation of the intrinsic but inhibit activation of the extrinsic apoptotic pathway. Acts as an antiapoptotic protein through association with GSK3A/B and BIRC2 in an apoptosis antagonizing signaling complex; activation of death receptors promotes caspase-dependent cleavage of BIRC2 and DDX3X and relieves the inhibition. May be involved in mitotic chromosome segregation. Appears to be a prime target for viral manipulations. Hepatitis B virus (HBV) polymerase and possibly vaccinia virus (VACV) protein K7 inhibit IFN-beta induction probably by dissociating DDX3X from TBK1 or IKBKE. Is involved in hepatitis C virus (HCV) replication; the function may involve the association with HCV core protein. HCV core protein inhibits the IPS1-dependent function in viral RNA sensing and may switch the function from a INF-beta inducing to a HCV replication mode. Involved in HIV-1 replication. Acts as a cofactor for XPO1-mediated nuclear export of incompletely spliced HIV-1 Rev RNAs.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
Publication Abstract from PubMed
DEAD-box proteins utilize ATP to bind and remodel RNA and RNA-protein complexes. All DEAD-box proteins share a conserved core that consists of two RecA-like domains. The core is flanked by subfamily-specific extensions of idiosyncratic function. The Ded1/DDX3 subfamily of DEAD-box proteins is of particular interest as members function during protein translation, are essential for viability, and are frequently altered in human malignancies. Here, we define the function of the subfamily-specific extensions of the human DEAD-box protein DDX3. We describe the crystal structure of the subfamily-specific core of wild-type DDX3 at 2.2 A resolution, alone and in the presence of AMP or nonhydrolyzable ATP. These structures illustrate a unique interdomain interaction between the two ATPase domains in which the C-terminal domain clashes with the RNA binding surface. Destabilizing this interaction accelerates RNA duplex unwinding, suggesting it is present in solution and inhibitory for catalysis. We use this core fragment of DDX3 to test the function of two recurrent medulloblastoma variants of DDX3 and find that both inactivate the protein in vitro and in vivo. Taken together, these results redefine the structural and functional core of the DDX3 subfamily of DEAD-box proteins.
Autoinhibitory Interdomain Interactions and Subfamily-Specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3.,Floor SN, Condon KJ, Sharma D, Jankowsky E, Doudna JA J Biol Chem. 2015 Nov 23. pii: jbc.M115.700625. PMID:26598523[24]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Chao CH, Chen CM, Cheng PL, Shih JW, Tsou AP, Lee YH. DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor. Cancer Res. 2006 Jul 1;66(13):6579-88. PMID:16818630 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-2415
- ↑ Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH. DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control. Oncogene. 2006 Mar 30;25(14):1991-2003. PMID:16301996 doi:http://dx.doi.org/10.1038/sj.onc.1209239
- ↑ Franca R, Belfiore A, Spadari S, Maga G. Human DEAD-box ATPase DDX3 shows a relaxed nucleoside substrate specificity. Proteins. 2007 Jun 1;67(4):1128-37. PMID:17357160 doi:http://dx.doi.org/10.1002/prot.21433
- ↑ Sun M, Song L, Li Y, Zhou T, Jope RS. Identification of an antiapoptotic protein complex at death receptors. Cell Death Differ. 2008 Dec;15(12):1887-900. doi: 10.1038/cdd.2008.124. Epub 2008, Oct 10. PMID:18846110 doi:http://dx.doi.org/10.1038/cdd.2008.124
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- ↑ Schroder M, Baran M, Bowie AG. Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J. 2008 Aug 6;27(15):2147-57. doi: 10.1038/emboj.2008.143. Epub 2008 Jul 17. PMID:18636090 doi:http://dx.doi.org/10.1038/emboj.2008.143
- ↑ Lai MC, Lee YH, Tarn WY. The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol Biol Cell. 2008 Sep;19(9):3847-58. doi: 10.1091/mbc.E07-12-1264. Epub 2008, Jul 2. PMID:18596238 doi:http://dx.doi.org/10.1091/mbc.E07-12-1264
- ↑ Lee CS, Dias AP, Jedrychowski M, Patel AH, Hsu JL, Reed R. Human DDX3 functions in translation and interacts with the translation initiation factor eIF3. Nucleic Acids Res. 2008 Aug;36(14):4708-18. doi: 10.1093/nar/gkn454. Epub 2008, Jul 15. PMID:18628297 doi:http://dx.doi.org/10.1093/nar/gkn454
- ↑ Shih JW, Tsai TY, Chao CH, Wu Lee YH. Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene. 2008 Jan 24;27(5):700-14. Epub 2007 Jul 30. PMID:17667941 doi:http://dx.doi.org/10.1038/sj.onc.1210687
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- ↑ Oshiumi H, Sakai K, Matsumoto M, Seya T. DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential. Eur J Immunol. 2010 Apr;40(4):940-8. doi: 10.1002/eji.200940203. PMID:20127681 doi:http://dx.doi.org/10.1002/eji.200940203
- ↑ Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z. Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3. J Gen Virol. 2010 Aug;91(Pt 8):2080-90. doi: 10.1099/vir.0.020552-0. Epub 2010, Apr 7. PMID:20375222 doi:http://dx.doi.org/10.1099/vir.0.020552-0
- ↑ Lai MC, Chang WC, Shieh SY, Tarn WY. DDX3 regulates cell growth through translational control of cyclin E1. Mol Cell Biol. 2010 Nov;30(22):5444-53. doi: 10.1128/MCB.00560-10. Epub 2010 Sep , 13. PMID:20837705 doi:http://dx.doi.org/10.1128/MCB.00560-10
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- ↑ Pek JW, Kai T. DEAD-box RNA helicase Belle/DDX3 and the RNA interference pathway promote mitotic chromosome segregation. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12007-12. doi:, 10.1073/pnas.1106245108. Epub 2011 Jul 5. PMID:21730191 doi:http://dx.doi.org/10.1073/pnas.1106245108
- ↑ Shih JW, Wang WT, Tsai TY, Kuo CY, Li HK, Wu Lee YH. Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response. Biochem J. 2012 Jan 1;441(1):119-29. doi: 10.1042/BJ20110739. PMID:21883093 doi:http://dx.doi.org/10.1042/BJ20110739
- ↑ Choi YJ, Lee SG. The DEAD-box RNA helicase DDX3 interacts with DDX5, co-localizes with it in the cytoplasm during the G2/M phase of the cycle, and affects its shuttling during mRNP export. J Cell Biochem. 2012 Mar;113(3):985-96. doi: 10.1002/jcb.23428. PMID:22034099 doi:http://dx.doi.org/10.1002/jcb.23428
- ↑ Geissler R, Golbik RP, Behrens SE. The DEAD-box helicase DDX3 supports the assembly of functional 80S ribosomes. Nucleic Acids Res. 2012 Jun;40(11):4998-5011. doi: 10.1093/nar/gks070. Epub 2012 , Feb 9. PMID:22323517 doi:http://dx.doi.org/10.1093/nar/gks070
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- ↑ Floor SN, Condon KJ, Sharma D, Jankowsky E, Doudna JA. Autoinhibitory Interdomain Interactions and Subfamily-Specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3. J Biol Chem. 2015 Nov 23. pii: jbc.M115.700625. PMID:26598523 doi:http://dx.doi.org/10.1074/jbc.M115.700625
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