PROSITE documentation PDOC50507

RNA-directed RNA polymerase catalytic domain profiles

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 organization has been likened to the shape of a right hand with three subdomains termed fingers, palm and thumb (see <PDB:1RDR>) [4]. Only the palm subdomain, composed of a four-stranded antiparallel β-sheet with two α-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 synthesized rather than DNA [5].

RNA viruses with no DNA stage can be placed in three main categories based on their replication and coding strategies: positive single-stranded RNA (ssRNA), negative ssRNA and double-stranded RNA (dsRNA) viruses. To recognize RNA-directed RNA polymerase we have developed six profiles that roughly follow this classification (see below). They are all directed against the catalytic region (palm subdomain).