The NYN Domains: Novel Predicted RNAses with a PIN Domain-Like Fold

Using sensitive sequence profile searches and contextual information gleaned fromdomain architectures and predicted operons we identify a novel family of proteindomains with predicted ribonuclease activity. These domains are found in theeukaryotic proteins typified by the Nedd4-binding protein 1 and the bacterial YacPlikeproteins (Nedd4-BP1, YacP nucleases; NYN domains). We show that the NYNdomain shares a common protein fold with two other previously characterized groupsof nucleases, namely the PIN (PilT N-terminal) and FLAP/5’->3’ exonucleasesuperfamilies. We also show that all these proteins share a common set of 4 acidicconserved residues that are predicted to constitute their active site. Based on theconservation of the acidic residues and structural elements we suggest that that PINand NYN domains are likely to bind only a single metal ion, unlike the FLAP/5’->3’exonuclease superfamily, which binds two metal ions. We also present evidence thatthe other conserved residues shared by all these three domains are likely to playcritical roles in sensing the substrate and positioning the catalytic residues in theright conformation. Based on conserved gene neighborhoods we infer that thebacterial members are likely to be components of the processome/degradsome thatprocess tRNAs or ribosomal RNAs. Eukaryotic versions appear to have undergoneextensive functional diversification as suggested by the several distinctive multidomainarchitectures showing fusions with various other RNA-binding domains likeCCCH, PPR and KH domains. Interestingly, the eukaryotic NYN domains also showmultiple fusions to the UBA domain, an ubiquitin-binding adaptor domain. Thisobservation, together with the mono-ubiquitination of Nedd4-BP1 by the ubiquitinligase Nedd4 suggests that the NYN domain proteins of eukaryotes are regulated bymono-ubiquitination. Given the localization of Nedd4-BP1 to punctuate nuclearbodies, it is likely that they are parts of nuclear RNA-processing complexes that aredependent on mono-ubiquitination for their assembly.

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