Differential action of natural selection on the N and C-terminal domains of 2'-5' oligoadenylate synthetases and the potential nuclease function of the C-terminal domain.
2'-5' Oligoadenylate synthetases (OAS) are a family of enzymes, which are best known for their important role in interferon-dependent antiviral mechanisms, but are also involved in the regulation of apoptosis, cell growth and differentiation in vertebrates. These enzymes bind double-stranded RNA and catalyze the synthesis of 2'-5' oligoadenylates from ATP. Several 2'-5' oligoadenylate synthetase-like proteins, which lack the ability to synthesize 2'-5' A, have been recently identified in humans and mice; the functions of these inactivated OAS derivatives remain unknown. Examination of phylogenetic trees shows that OAS inactivation in mammals occurred on several independent occasions. Comparative sequence analysis of OAS, poly(A)-polymerases, TRF4/sigma-family polymerases, archaeal CCA-adding enzymes and uridilyltransferases from trypanosomes resulted in the identification of a C-terminal domain, which is conserved in all these enzymes and is distinct from the nucleotidyltransferase domain. Secondary structure prediction shows that this domain has a four-helix core, which is most closely related to the ATP-cone domain, a regulatory nucleotide-binding domain present in ribonucleotide reductases and several other enzymes and transcription regulators. These observations, taken together with the experimental evidence of nuclease activity in the TRF4/sigma-family of polymerases, suggest that the C-terminal domain of OAS and their homologs might have nuclease activity. The putative nuclease domain is preferentially conserved in OAS derivatives that lack an active nucleotidyltransferase domain and, as indicated by the analysis of the ratio of synonymous to non-synonymous substitutions, appears to be subject to purifying selection in these proteins. In contrast, phylogenetic analysis provided evidence of episodic positive selection in the mouse OAS-like proteins with inactivated nucleotidyltransferase domains, which suggests that some of these proteins might have distinct antiviral functions.
Rogozin
Igor B
IB
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Aravind
L
L
Koonin
Eugene V
EV
D015088:2',5'-Oligoadenylate Synthetase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D003851:Deoxyribonucleases / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D007372:Interferons; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D000998:Antiviral Agents; D020033:Protein Isoforms; D000255:Adenosine Triphosphate; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; D003851:Deoxyribonucleases