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Abstract
DEAD-box helicases (DDXs) regulate RNA processing and metabolism by unwinding short double-stranded (ds) RNAs. Sharing a helicase core composed of two RecA-like domains (D1D2), DDXs function in an ATP-dependent, non-processive manner. As an attractive target for cancer and AIDS treatment, DDX3X and its orthologs are extensively studied, yielding a wealth of biochemical and biophysical data, including structures of apo-D1D2 and post-unwound D1D2:single-stranded RNA complex, and the structure of a D2:dsRNA complex that is thought to represent a pre-unwound state. However, the structure of a pre-unwound D1D2:dsRNA complex remains elusive, and thus, the mechanism of DDX action is not fully understood. Here, we describe the structure of a D1D2 core in complex with a 23-base pair dsRNA at pre-unwound state, revealing that two DDXs recognize a 2-turn dsRNA, each DDX mainly recognizes a single RNA strand, and conformational changes induced by ATP binding unwinds the RNA duplex in a cooperative manner.
Highlights
DEAD-box helicases (DDXs) regulate RNA processing and metabolism by unwinding short double-stranded RNAs
Since unwinding occurs once ATP is bound to the DDX:double-stranded RNA (dsRNA) complex[3,12,21], we performed crystallization trials using the minimal, subfamily-specific functional core of DDX3X, in the absence of ATP and AMPPNP
Our structure shows that the two D1D2 cores jointly recognize base pairs 1–22 of the 26-bp dsRNA so that the resulting complex is not symmetric (Supplementary Fig. 2a)
Summary
DEAD-box helicases (DDXs) regulate RNA processing and metabolism by unwinding short double-stranded (ds) RNAs. Sharing a helicase core composed of two RecA-like domains (D1D2), DDXs function in an ATP-dependent, non-processive manner. We describe the structure of a D1D2 core in complex with a 23-base pair dsRNA at pre-unwound state, revealing that two DDXs recognize a 2-turn dsRNA, each DDX mainly recognizes a single RNA strand, and conformational changes induced by ATP binding unwinds the RNA duplex in a cooperative manner. DDX3X and its yeast ortholog Ded1p represent a subfamily of DDX, which is closely related to the subfamily represented by human DDX4 and fly Vasa (Supplementary Fig. 1)[2]. Like all DDXs, DDX3X contains a helicase core composed of two RecA-. Inhibitors of DDX3X have been developed for cancer treatment[8,9,10]
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