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

详细信息    查看全文

• 作者：Hao Huang ; Elton Zeqiraj ; Beihua Dong ; Babal聽Kant Jha ; Nicole聽M. Duffy ; Stephen Orlicky ; Neroshan Thevakumaran ; Manisha Talukdar ; Monica聽C. Pillon ; Derek聽F. Ceccarelli ; Leo聽C.K. Wan ; Yu-Chi Juang ; Daniel聽Y.L. Mao ; Christina Gaughan ; Margo聽A. Brinton ; Andrey聽A. Perelygin ; Igor Kourinov ; Alba Guarn茅 ; Robert聽H. Silverman ; Frank Sicheri
• 刊名：Molecular Cell
• 出版年：23 January, 2014
• 年：2014
• 卷：53
• 期：2
• 页码：221-234
• 全文大小：4267 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

RNase L is an ankyrin repeat domain-containing dual endoribonuclease-pseudokinase that is activated by unusual 2,鈥?鈥?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聽脜 and 3.25聽脜 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.