Format

Send to

Choose Destination
Structure. 2015 May 5;23(5):851-862. doi: 10.1016/j.str.2015.03.012. Epub 2015 Apr 16.

The Activation Mechanism of 2'-5'-Oligoadenylate Synthetase Gives New Insights Into OAS/cGAS Triggers of Innate Immunity.

Author information

1
Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
2
Institute for Virology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
3
Research Division for Structural Analysis, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
4
Institute of Protein Research, Russian Academy of Science, 142290 Pushchino, Moscow Region, Russian Federation.
5
Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; Research Division for Structural Analysis, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
6
Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; Research Division for Structural Analysis, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Electronic address: fedorov.roman@mh-hannover.de.

Abstract

2'-5'-Oligoadenylate synthetases (OASs) produce the second messenger 2'-5'-oligoadenylate, which activates RNase L to induce an intrinsic antiviral state. We report on the crystal structures of catalytic intermediates of OAS1 including the OAS1·dsRNA complex without substrates, with a donor substrate, and with both donor and acceptor substrates. Combined with kinetic studies of point mutants and the previously published structure of the apo form of OAS1, the new data suggest a sequential mechanism of OAS activation and show the individual roles of each component. They reveal a dsRNA-mediated push-pull effect responsible for large conformational changes in OAS1, the catalytic role of the active site Mg(2+), and the structural basis for the 2'-specificity of product formation. Our data reveal similarities and differences in the activation mechanisms of members of the OAS/cyclic GMP-AMP synthase family of innate immune sensors. In particular, they show how helix 3103-α5 blocks the synthesis of cyclic dinucleotides by OAS1.

PMID:
25892109
DOI:
10.1016/j.str.2015.03.012
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center