Journal Article Structural basis for the regulation of enzymatic activity of Regnase-1 by domain-domain interactions

Yokogawa, Mariko  ,  Tsushima, Takashi  ,  Noda, Nobuo N.  ,  Kumeta, Hiroyuki  ,  Enokizono, Yoshiaki  ,  Yamashita, Kazuo  ,  Standley, Daron M.  ,  Takeuchi, Osamu  ,  Akira, Shizuo  ,  Inagaki, Fuyuhiko

62016-03-01 , Nature Publishing Group
Regnase-1 is an RNase that directly cleaves mRNAs of inflammatory genes such as IL-6 and IL-12p40, and negatively regulates cellular inflammatory responses. Here, we report the structures of four domains of Regnase-1 from Mus musculus - the N-terminal domain (NTD), PilT N-terminus like (PIN) domain, zinc finger (ZF) domain and C-terminal domain (CTD). The PIN domain harbors the RNase catalytic center; however, it is insufficient for enzymatic activity. We found that the NTD associates with the PIN domain and significantly enhances its RNase activity. The PIN domain forms a head-to-tail oligomer and the dimer interface overlaps with the NTD binding site. Interestingly, mutations blocking PIN oligomerization had no RNase activity, indicating that both oligomerization and NTD binding are crucial for RNase activity in vitro. These results suggest that Regnase-1 RNase activity is tightly controlled by both intramolecular (NTD-PIN) and intermolecular (PIN-PIN) interactions.

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