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

Mariko Yokogawa1, Takashi Tsushima2, Nobuo N Noda3

  • 1Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan.

Scientific Reports
|March 2, 2016
PubMed

Insights

Regnase-1, an RNase regulating inflammation, requires both N-terminal domain (NTD) binding and PIN domain oligomerization for its enzymatic activity. These interactions are crucial for controlling cellular inflammatory responses.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Regnase-1 is a key RNase that regulates cellular inflammatory responses by degrading inflammatory gene mRNAs.
  • Its enzymatic activity is essential for controlling inflammation, but the mechanisms governing its regulation are not fully understood.

Purpose of the Study:

  • To elucidate the structural basis of Regnase-1's RNase activity.
  • To investigate the roles of its distinct domains in enzymatic function and regulation.

Main Methods:

  • X-ray crystallography was used to determine the structures of four Regnase-1 domains: N-terminal domain (NTD), PilT N-terminus like (PIN) domain, zinc finger (ZF) domain, and C-terminal domain (CTD).
  • Biochemical assays were performed to assess RNase activity in the presence of various domain mutations and interactions.

Main Results:

  • The PIN domain contains the catalytic center but requires association with the NTD for significant RNase activity.
  • Regnase-1 forms head-to-tail oligomers through the PIN domain, and this oligomerization interface overlaps with the NTD binding site.
  • Mutations disrupting PIN oligomerization abolished RNase activity, highlighting the necessity of both NTD binding and PIN-PIN interactions.

Conclusions:

  • Regnase-1's RNase activity is tightly regulated by a combination of intramolecular (NTD-PIN) and intermolecular (PIN-PIN) interactions.
  • These findings provide critical insights into the structural mechanisms controlling Regnase-1 function in inflammatory pathways.

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