• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • Interestingly it was recently reported that the formation of


    Interestingly, it was recently reported that the formation of a Ded1–CRM1–RanGTP trimeric complex in yeast resulted in a reduced RNA-stimulated ATPase activity of Ded1 [43]. This phenomenon was dependent on the NES present in Ded1 and occurred concomitantly with the increase in the Km for the RNA substrate suggesting that the NES-dependent interaction between Ded1 and CRM1–RanGTP may modulate substrate specificity of the RNA helicase [43]. Although the interaction between human DDX3 and CRM1 seems not to rely on a NES [3], it would be interesting to determine whether such a modulation of the enzymatic activity of DDX3 also occurs in the presence of the RRE/Rev–CRM1–RanGTP complex. Thus, it is tempting to speculate that DDX3 (and Ded1) could be acting on the CRM1-dependent pathway analogously to Dbp5 in the NXF1-dependent nuclear export pathway [44]. As suggested by previous data [45], we identified that the N-terminal and C-terminal domains of DDX3 were enriched in intrinsically disordered regions (Fig. 6). We also found that this characteristic was conserved in the external domains of several homologs of DDX3 (from yeast to human) and all described human DEAD-box proteins. DEAD-box helicases play Phorbol 12,13-dibutyrate functions within the cell by remodeling RNA:RNA and RNA:protein complexes or by functioning as RNA clamps for the assembly of large macromolecular complexes. Despite the high degree of conservation of the catalytic core and the mechanisms of RNA binding and ATP binding/hydrolysis in several members of the family, their functions are rather non-redundant probably due to the substrate specificity conferred by the N- and/or C-terminal domains surrounding the helicase core. Interestingly, several RNA helicases, including DDX3, have been identified as components of different RNP complexes and thus, associated with different biological processes involving RNA [2], [15]. The presence of intrinsically disordered regions within the N- and C-termini may confer DEAD-box proteins the flexibility needed to interact with different partners in different RNP complexes in a spatiotemporal manner. In the case of DDX3, the N-terminal domain allows interaction with the VACV K7 protein [35], eIF4E [36], IRF3 [38] and to be included in a complex together with CRM1 (Fig. 5), indicating an important role of this domain in establishing multiple interactions. Moreover, the N-terminal domain regulates the RNA-stimulated ATPase activity [11], stress granule assembly [37] and HIV-1 unspliced mRNA translation (Fig. 1) also indicating an important role of the N-terminal domain in regulating biological processes driven by this enzyme. Given the fact that neither the NES nor the eIF4E-binding domain seems to be involved in DDX3 function during HIV-1 gene expression (Fig. 6) [5], [6], it is tempting to speculate that the intrinsically disordered N-terminal domain of DDX3 may first confer the ability to be incorporated into the CRM1-exported viral mRNP at the nuclear envelope and then the flexibility to promote the transition from an export mRNP to a translation one.