Xenbase Image ID: 127437

Figure 6. Schematic model of Lin28-mediated binding and inhibition of pre-let-7 maturation. In the absence of Lin28, the PAZ domain of Dicer recognizes the 2 nt 3′-overhang of pre-let-7 and cleaves the substrate about 22 nt from the end (Dicer cleavage site, indicated by dark red arrows). In the presence of Lin28, the CSD first binds with its preformed nucleic acid-binding platform to pyrimidine-containing single-stranded parts in the terminal loop (preE) of pre-let-7. In a fast reaction, the CSD then remodels the preE region and melts a part of the upper stem region including the Dicer cleavage site. As the binding of Lin28 to pre-let-7 is highly cooperative, the remodeling of pre-let-7 may be facilitated in trans by another Lin28 molecule. Once the conserved GGAG is freely accessible, the Lin28 ZKD mediates a specific binding to this motif and anchors Lin28 in this position. This second reaction is rather slow, as both the ZKD and the flexible basic linker between the domains have to perform larger conformational changes as judged from apo and nucleotide-bound structures. As a consequence, the Dicer cleavage site remains constantly open, and Lin28 inhibits the cleavage by Dicer. The sequence-specific interaction via the ZKD thus ensures a directional positioning of Lin28 to pre-let-7, which may allow promoting the terminal uridylation of pre-let-7 by TUT4/Zcchc11 or PUP-2. Image published in: Mayr F et al. (2012) © The Author(s) 2012. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license Larger Image Printer Friendly View

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