Crystal structure of the 2'-specific and double-stranded RNA-activated interferon-induced antiviral protein 2'-5'-oligoadenylate synthetase.
2'-5'-oligoadenylate synthetases are interferon-induced, double-stranded RNA-activated antiviral enzymes which are the only proteins known to catalyze 2'-specific nucleotidyl transfer. This crystal structure of a 2'-5'-oligoadenylate synthetase reveals a structural conservation with the 3'-specific poly(A) polymerase that, coupled with structure-guided mutagenesis, supports a conserved catalytic mechanism for the 2'- and 3'-specific nucleotidyl transferases. Comparison with structures of other superfamily members indicates that the donor substrates are bound by conserved active site features while the acceptor substrates are oriented by nonconserved regions. The 2'-5'-oligoadenylate synthetases are activated by viral double-stranded RNA in infected cells and initiate a cellular response by synthesizing 2'-5'-oligoadenylates, which in turn activate RNase L. This crystal structure suggests that activation involves a domain-domain shift and identifies a putative dsRNA activation site that is probed by mutagenesis, thus providing structural insight into cellular recognition of viral double-stranded RNA.
Hartmann
Rune
R
Department of Molecular Cardiology and Center for Structural Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Justesen
Just
J
Sarkar
Saumendra N
SN
Sen
Ganes C
GC
Yee
Vivien C
VC
D015088:2',5'-Oligoadenylate Synthetase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism*; D016415:Sequence Alignment; D013552:Swine
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase