Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity Academic Article uri icon

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abstract

  • RNase L is an ankyrin repeat domain-containing dual endoribonuclease-pseudokinase that is activated by unusual 2,'5'-oligoadenylate (2-5A) second messengers and which impedes viral infections in higher vertebrates. Despite its importance in interferon-regulated antiviral innate immunity, relatively little is known about its precise mechanism of action. Here we present a functional characterization of 2.5 Å and 3.25 Å X-ray crystal and small-angle X-ray scattering structures of RNase L bound to a natural 2-5A activator with and without ADP or the nonhydrolysable ATP mimetic AMP-PNP. These studies reveal how recognition of 2-5A through interactions with the ankyrin repeat domain and the pseudokinase domain, together with nucleotide binding, imposes a rigid intertwined dimer configuration that is essential for RNase catalytic and antiviral functions. The involvement of the pseudokinase domain of RNase L in 2-5A sensing, nucleotide binding, dimerization, and ribonuclease functions highlights the evolutionary adaptability of the eukaryotic protein kinase fold.

authors

  • Guarne, Alba
  • Huang, Hao
  • Zeqiraj, Elton
  • Dong, Beihua
  • Jha, Babal Kant
  • Duffy, Nicole M
  • Orlicky, Stephen
  • Thevakumaran, Neroshan
  • Talukdar, Manisha
  • Pillon, Monica C
  • Ceccarelli, Derek F
  • Wan, Leo CK
  • Juang, Yu-Chi
  • Mao, Daniel YL
  • Gaughan, Christina
  • Brinton, Margo A
  • Perelygin, Andrey A
  • Kourinov, Igor
  • Guarné, Alba
  • Silverman, Robert H
  • Sicheri, Frank

publication date

  • January 2014

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