Abstract
During the asymmetric division of Drosophila neuroblasts (NBs), the scaffold Miranda (Mira) coordinates the subcellular distribution of cell-fate determinants including Staufen (Stau) and segregates them into the ganglion mother cells (GMCs). Here we show the fifth double-stranded RNA (dsRNA)-binding domain (dsRBD5) of Stau is necessary and sufficient for binding to a coiled-coil region of Mira cargo-binding domain (CBD). The crystal structure of Mira514–595/Stau dsRBD5 complex illustrates that Mira forms an elongated parallel coiled-coil dimer, and two dsRBD5 symmetrically bind to the Mira dimer through their exposed β-sheet faces, revealing a previously unrecognized protein interaction mode for dsRBDs. We further demonstrate that the Mira–Stau dsRBD5 interaction is responsible for the asymmetric localization of Stau during Drosophila NB asymmetric divisions. Finally, we find the CBD-mediated dimer assembly is likely a common requirement for Mira to recognize and translocate other cargos including brain tumour (Brat).
Highlights
During the asymmetric division of Drosophila neuroblasts (NBs), the scaffold Miranda (Mira) coordinates the subcellular distribution of cell-fate determinants including Staufen (Stau) and segregates them into the ganglion mother cells (GMCs)
One daughter cell is a copy of the mother cell retaining self-renewal ability, and the other daughter cell enters the path of differentiation[5]
While the basal localization of Pros, brain tumour (Brat) and Stau is facilitated by their binding to the scaffold protein Mira[16,20,21,22], the asymmetric localization of Numb is mediated by its adaptor Partner of Numb (Pon)[23]
Summary
During the asymmetric division of Drosophila neuroblasts (NBs), the scaffold Miranda (Mira) coordinates the subcellular distribution of cell-fate determinants including Staufen (Stau) and segregates them into the ganglion mother cells (GMCs). Each ACD of NB generates a self-renewing NB and a smaller GMC that initiates differentiation[6] During this process, protein complexes containing cell fate determinants localize asymmetrically to the basal cell cortex during mitosis and are segregated preferentially into the GMC daughter after cytokinesis[7]. The central CBD of Mira (aa 460–668) has been identified as the binding region for cargo proteins Pros, Brat and Stau[14,20,24], and was predicted to form a parallel coiled-coil dimer through biochemical and biophysical characterizations[28]. Recent findings that mouse STAU2 regulates Prox[1] (Pros homologue) mRNA and Trim[32] (Brat homologue) mRNA asymmetric localization have demonstrated the conserved role of Stau proteins in neurogenesis[31,32]. As yet there lacks a clear structure illustrating the trans dsRBD– protein interactions other than dsRBD–dsRBD dimerization
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