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The organization and contribution of helicases to RNA splicing

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Splicing is an essential step of gene expression. It occurs in two consecutive chemical reactions catalyzed by a large protein–RNA complex named the spliceosome. Assembled on the pre‐mRNA substrate from five small nuclear proteins, the spliceosome acts as a protein‐controlled ribozyme to catalyze the two reactions and finally dissociates into its components, which are re‐used for a new round of splicing. Upon following this cyclic pathway, the spliceosome undergoes numerous intermediate stages that differ in composition as well as in their internal RNA–RNA and RNA–protein contacts. The driving forces and control mechanisms of these remodeling processes are provided by specific molecular motors called RNA helicases. While eight spliceosomal helicases are present in all organisms, higher eukaryotes contain five additional ones potentially required to drive a more intricate splicing pathway and link it to an RNA metabolism of increasing complexity. Spliceosomal helicases exhibit a notable structural diversity in their accessory domains and overall architecture, in accordance with the diversity of their task‐specific functions. This review summarizes structure–function knowledge about all spliceosomal helicases, including the latter five, which traditionally are treated separately from the conserved ones. The implications of the structural characteristics of helicases for their functions, as well as for their structural communication within the multi‐subunits environment of the spliceosome, are pointed out. WIREs RNA 2016, 7:259–274. doi: 10.1002/wrna.1331 This article is categorized under: RNA-Based Catalysis > RNA Catalysis in Splicing and Translation RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Processing > Splicing Mechanisms
Helicases in the splicing cycle. Stages where the eight conserved helicases act are indicated in parentheses. Recruitment of additional human helicases is depicted. Note that SF3b125 is found only in trace amounts and is therefore shown with a dashed outline (adapted with modifications from Will and Lührmann).
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Timeline history of structure determination of spliceosomal helicases.
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Structural communication in helicases and complexes with other splicing factors. (a) The C‐terminal tail of Prp8 (Jab1 domain) runs across the canonical RNA‐binding motifs of Brr2, inhibiting its helicase activity. (b) Relative orientation of Aquarius's ARM and RecA domains (left) resembles the one observed between RecA domains of eIF4AIII and HEAT‐repeat protein Cwc22 (right).
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Structural diversity of spliceosomal helicases. (a) DEAD‐box helicases in various conformations. Ribbon plots and schematic representations of Prp5 (PDB 4LJY), Prp28 (PDB 4W7S), UAP56 (PDB 1XTI), and eIF4AIII (PDB 2XB2) are shown. RNA is depicted as a green line and ANP as a red hexagon. ANP is a non‐hydrolysable ATP analogue. (b) Ribbon representation of crystal structures of Prp43 (PDB 2XAU), Brr2 (PDB 4F91), and Aquarius (PDB 4PJ3). Ribbon representation of the canonical helicase core of Aquarius (in the center, PDB 4PJ3) with assigned conserved sequence motifs of RecA1 (I, Ia‐c, II, III and Q) and RecA2 (IIIa, IV, V, Va‐b and VI) domains. Motifs are colored according to their predominant function: red, nucleotide binding/hydrolysis; green, nucleic‐acid binding; blue, communication between nucleotide‐ and RNA‐binding sites. Accessory domains are shown around the helicase core.
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Structures of domains from spliceosomal helicases. Ribbon representation of the canonical helicase core of Aquarius (in the center, PDB 4PJ3) with assigned conserved sequence motifs of RecA1 (I, Ia‐c, II, III and Q) and RecA2 (IIIa, IV, V, Va‐b and VI) domains. Motifs are colored according to their predominant function: red, nucleotide binding/hydrolysis; green, nucleic‐acid binding; blue, communication between nucleotide‐ and RNA‐binding sites. Accessory domains are shown around the helicase core.
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Domain organisation of spliceosomal helicases. Helicases are grouped according to their subfamily. Domains: RecA1 and RecA2, helicase core; RS, arginine/serine rich; PWI, proline/tryptophan/isoleucine tripeptide; WH, winged helix; R/D, ratchet domain; HLH, helix‐loop‐helix; IG, Ig‐like; OB, oligonucleotide/oligosaccharide‐binding; ARM, armadillo repeat. Regions of determined structures are underlined. H.s. – Homo sapiens; S.c. – Saccharomyces cerevisiae. In human, the conserved spliceosomal helicases are also named: DDX46 (Prp5), U5‐100K/DDX23 (Prp28), U5‐200K (Brr2), DHX16 (Prp2), DHX38 (Prp16), DHX8 (Prp22) and DHX15 (Prp43).
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA-Based Catalysis > RNA Catalysis in Splicing and Translation
RNA Processing > Splicing Mechanisms

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