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

作者：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 C K; Juang Yu Chi; Mao Daniel Y L; Gaughan Christina; Brinton Margo A; Perelygin Andrey A; Kourinov Igor; Guarne Alba; Silverman Robert H^*; Sicheri Frank

来源：Molecular Cell, 2014, 53(2): 221-234.

DOI：10.1016/j.molcel.2013.12.025

RNase L is an ankyrin repeat domain-containing dual endoribonuclease-pseudokinase that is activated by unusual 2,%26apos;5%26apos;-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 angstrom and 3.25 angstrom 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 non-hydrolysable 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.

• 出版日期2014-1-23