Helicases have been classified in 5 superfamilies (SF1-SF5) [1]. All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop) (see <PDOC00017>) and Walker B (Mg2+-binding aspartic acid) motifs [1]. Superfamily 4 helicase, related to bacterial dnaB proteins, comprises a relatively small compact family of proteins containing, in addition to Walker A and B, three distinct conserved motifs which are not present in other helicase superfamilies. SF4 is a hexameric helicase that function mainly in bacterial or bacteriophage DNA replication. It is intimately associated with other proteins of the replication fork. The helicase domain assembles into ring-shaped hexamers that encircle the lagging strand of the replication fork, moving in a 5' to 3' direction and displacing the complementary DNA strand in an unwinding reaction that is powered by nucleotide hydrolysis [2,3].

Several bacteriophage SF4 helicase domains have been crystalized (see for example <PDB:1CR0>) [4]. The central core is similar to the α-β RecA-like domain. The functional enzyme is arranged in a ring-shaped hexamer. A nucleotide binds in the crevice formed between adjacent subunits, where an arginine that is analogous to the arginine finger motif of GTPase-activating proteins (see <PDOC50238>) could trans-activate the bound nucleotide for hydrolysis. This nucleotide-binding site at the interface of two helicase domains is also a feature of other DNA helicase such as PcrA, Rep or NS3 proteins, and it could be a general mechanism for DNA unwinding activity [4].

Some proteins known to contain an SF4 helicase domain are listed below [5,6]:

• Bacterial dnaB protein. It unwinds the DNA duplex ahead of the replication fork and is also responsible for attracting the dnaG primase to the replication fork.
• Bacteriophage T7 gp4 and bacteriophage T4 gp41 proteins. They are bifunctional primase-helicases that unwind duplex DNA at the replication fork while initiating the synthesis of Okazaki fragments on the lagging strand.
• Metazoan Twinkle proteins. In human, Twinkle is a helicase involved in mitochondrial DNA replication. It has been implicated in autosomal dominant progressive external ophthalmoplegia (adPEO), a mitochondrial disorder characterized by mtDNA deletions [7].
• Several Cryptophyta and Viridiplantae hypothetical proteins that also contain a primase domain.
• Several protozoan hypothetical proteins that also contain a primase domain or an exonuclease domain.
• Rhodophyta chloroplastic dnaB-like proteins.

The profile we developed covers the entire SF4 helicase domain.

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