InterPro: IPR007099 RNA-directed RNA polymerase, negative-strand RNA virus

RNA-directed RNA polymerase (RdRp) (EC:2.7.7.48) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage [1, 2]. It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear. The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product [3].

All the RNA-directed RNA polymerases, and many DNA-directed polymerases, employ a fold whose organisation has been likened to the shape of a right hand with three subdomains termed fingers, palm and thumb [4]. Only the palm subdomain, composed of a four-stranded antiparallel beta-sheet with two alpha-helices, is well conserved among all of these enzymes. In RdRp, the palm subdomain comprises three well conserved motifs (A, B and C). Motif A (D-x(4,5)-D) and motif C (GDD) are spatially juxtaposed; the Asp residues of these motifs are implied in the binding of Mg2+ and/or Mn2+. The Asn residue of motif B is involved in selection of ribonucleoside triphosphates over dNTPs and thus determines whether RNA is synthesised rather than DNA [5]. The domain organisation [6] and the 3D structure of the catalytic centre of a wide range of RdPp's, even those with a low overall sequence homology, are conserved. The catalytic centre is formed by several motifs containing a number of conserved amino acid residues.

There are 4 superfamilies of viruses that cover all RNA containing viruses with no DNA stage:

• Viruses containing positive-strand RNA or double-strand RNA, except retroviruses and Birnaviridae: viral RNA-directed RNA polymerases including all positive-strand RNA viruses with no DNA stage, double-strand RNA viruses, and the Cystoviridae, Reoviridae, Hypoviridae, Partitiviridae, Totiviridae families.
• Mononegavirales (negative-strand RNA viruses with non-segmented genomes).
• Negative-strand RNA viruses with segmented genomes, i.e. Orthomyxoviruses (including influenza A, B, and C viruses, Thogotoviruses, and the infectious salmon anemia virus), Arenaviruses, Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tenuiviruses and Tospoviruses.
• Birnaviridae family of dsRNA viruses.

• All positive-strand RNA eukaryotic viruses with no DNA stage.
• All RNA-containing bacteriophages -there are two families of RNA-containing bacteriophages: Leviviridae (positive ssRNA phages) and Cystoviridae (dsRNA phages).
• Reoviridae family of dsRNA viruses.

This entry corresponds to a relatively conserved segment of 147 - 180 aa of RdRp or its catalytic subunit. The proteins in this family are: RNA polymerase PB1 subunits of Orthomyxoviruses and RNA polymerases (L proteins) of Arenaviruses, Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tenuiviruses and Tospoviruses.