Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782310067009224704 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3974923 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT huanghao dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT zeqirajelton dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT dongbeihua dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT jhababalkant dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT duffynicolem dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT orlickystephen dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT thevakumaranneroshan dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT talukdarmanisha dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT pillonmonicac dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT ceccarelliderekf dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT wanleock dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT juangyuchi dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT maodanielyl dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT gaughanchristina dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT brintonmargoa dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT perelyginandreya dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT kourinovigor dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT guarnealba dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT silvermanroberth dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity AT sicherifrank dimericstructureofpseudokinasernaselboundto25arevealsabasisforinterferoninducedantiviralactivity |