DEAD-box helicases: posttranslational regulation and function.

Helicases are enzymes that can separate duplex oligonucleotides in a NTP-dependent fashion and are essential in all aspects of DNA and RNA metabolism. Amino acid sequence analysis identified several conserved sequence motifs in DNA and RNA helicases allowing their classification into five major groups (Super families SF1–SF5) [1]. DExD/H helicases share eight conserved sequence motifs, whereas the DEAD-box helicase subgroup has an additional ninth conserved sequence motif [2]. These sequence motifs encompass an approximately 300–400 amino acid core region involved in ATP-binding/hydrolysis and RNA binding (Part 2: Fig. 1). Structural analyses of several DEAD-box proteins show this core region forms two RecA-like globular domains [2]. Work in a variety of eukaryotes has identified the biological functions of many DEAD-box helicases. The genome of the yeast Saccharomyces cerevisiae encodes 25 DEAD-box proteins. Counterparts for each of these, along with 11 additional DEAD-box genes, are found in the human genome. Although some of the shared DEAD-box genes have similar functions in both humans and yeast, it is clear that several human DEAD-box proteins have acquired additional functions [3,4]. How these functions are regulatedwithin cellular or developmental contexts is less understood. The N-terminal and C-terminal sequences flanking the DEAD-box core regions are considerably more divergent among DEAD-box proteins and are thought to interact with RNA substrates or cofactors. Such interactions can thereby target and regulate their helicase activity or perform completely independent functions [3]. Although the structures of these divergent flanking sequences are largely unknown, a growing body of evidence suggests they are regulatory hot-spots for posttranslational modifications and protein–protein interactions (Fig. 1). Despite DEAD-box helicase conservation throughout the animal kingdom, the most comprehensive data on their posttranslational regulation comes from the human DEAD-box helicase family (DDX proteins). For the purposes of this review, we shall focus primarily on the data concerning human DDX proteins and look at our current understanding on how posttranslational modifications and protein–protein interactions regulate DEAD-box protein functions.