Dimeric structure of pseudokinase RNase L bound to 2-5A reveals a basis for interferon induced antiviral activity

Details

• Alternative Title:
  Mol Cell
• Personal Author:
  Huang, Hao ; Zeqiraj, Elton ; Dong, Beihua ; Jha, Babal Kant ; Duffy, Nicole ; Orlicky, Stephen ; Thevakumaran, Neroshan ; Talukdar, Manisha ; Pillon, Monica C. ; Ceccarelli, Derek F. ; Wan, Leo ; Juang, Yu-Chi ; Mao, Daniel Y.L. ; Gaughan, Christina ; Brinton, Margo A. ; Perelygin, Andrey A. ; Kourinov, Igor ; Guarné, Alba ; Silverman, Robert H. ; Sicheri, Frank
• 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.
• Subjects:
  Adenine Nucleotides Adenosine Diphosphate Adenylyl Imidodiphosphate Animals Ankyrin Repeat Article Binding Sites Crystallography, X-Ray Dimerization Encephalomyocarditis Virus Endoribonucleases HeLa Cells Humans Models, Molecular Mutagenesis, Site-Directed Oligoribonucleotides Picornaviridae Protein Structure, Tertiary Scattering, Radiation Structure-Activity Relationship Sus Scrofa

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• Source:
  Mol Cell. 2014; 53(2):221-234
• Pubmed ID:
  24462203
• Pubmed Central ID:
  PMC3974923
• Document Type:
  Journal Article
• Funding:
  P41 GM103403/GM/NIGMS NIH HHSUnited States/ ; R01 AI045135/AI/NIAID NIH HHSUnited States/ ; AI045135/AI/NIAID NIH HHSUnited States/ ; R01 CI000216/CI/NCPDCID CDC HHSUnited States/ ; R01 CA044059/CA/NCI NIH HHSUnited States/ ; MOP-84370/CAPMC/ CIHRCanada/ ; P41GM103403/GM/NIGMS NIH HHSUnited States/ ; CA044059/CA/NCI NIH HHSUnited States/ ; 092381/Wellcome TrustUnited Kingdom/
• Volume:
  53
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d8dfaa9970f82683e381f5f35ee0b0d5e684a4c26b533a7df4ad856c8c8d211e
• Download URL:
  https://stacks.cdc.gov/view/cdc/34111/cdc_34111_DS1.pdf
• File Type:
  [PDF - 1.61 MB ]