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

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...

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Autores principales: 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, Guarné, Alba, Silverman, Robert H., Sicheri, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974923/
https://www.ncbi.nlm.nih.gov/pubmed/24462203
http://dx.doi.org/10.1016/j.molcel.2013.12.025
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author 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
Guarné, Alba
Silverman, Robert H.
Sicheri, Frank
author_facet 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
Guarné, Alba
Silverman, Robert H.
Sicheri, Frank
author_sort Huang, Hao
collection PubMed
description 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.
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spelling pubmed-39749232015-01-23 Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity 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 Guarné, Alba Silverman, Robert H. Sicheri, Frank Mol Cell Article 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. Elsevier Inc. 2014-01-23 2014-01-23 /pmc/articles/PMC3974923/ /pubmed/24462203 http://dx.doi.org/10.1016/j.molcel.2013.12.025 Text en Copyright © 2014 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
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
Guarné, Alba
Silverman, Robert H.
Sicheri, Frank
Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title_full Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title_fullStr Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title_full_unstemmed Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title_short Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity
title_sort dimeric structure of pseudokinase rnase l bound to 2-5a reveals a basis for interferon-induced antiviral activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974923/
https://www.ncbi.nlm.nih.gov/pubmed/24462203
http://dx.doi.org/10.1016/j.molcel.2013.12.025
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