The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

Tan, Jinzhi; Vonrhein, Clemens; Smart, Oliver S.; Bricogne, Gerard; Bollati, Michela; Kusov, Yuri; Hansen, Guido; Mesters, Jeroen R.; Schmidt, Christian L.; Hilgenfeld, Rolf

The target of SUD binding could be G-quadruplexes in RNA of viral or/and cellular origin. The SARS-CoV genome contains three G 6 -stretches (one on the plus-strand and two on the minusstrand) and an additional two G 5 -sequences, which could perhaps form local G-quadruplexes. However, the G-stretch binding capabilities of SUD and SUD core seem to have been optimized for recognition of longer G-rich sequences. By systematic variation of the length of oligo(dG), we found that SUD core exhibits strongest affinity (K D ,0.45 mM) for (dG) 10 to (dG) 14 [31] . The 39nontranslated regions of several host-cell mRNAs coding for proteins involved in the regulation of apoptosis and in signaling pathways contain long G-stretches and could also be targets of SUD. Examples of such mRNAs are those coding for the proapoptotic protein Bbc3 [45] , RAB6B (a member of the Ras oncogene family, [46] ), MAP kinase 1 [47] , and TAB3, a component of the NF-kB signaling pathway [48] . It is conceivable that these proteins might be targets for the virus when interfering with cellular signaling. Changes in the stability and/or translation efficiency of these mRNAs due to the binding of a viral regulatory factor could result in an altered reaction of the infected cell to apoptotic signals, or it could silence the antiviral response.