New Paper - A25 Mann

New publication from Carina Mann's group 

Structural basis for OAS2 regulation and its antiviral function

Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and are critical for
restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2′–5′-oligoadeny-
lates for RNase L activation. Existing structures of OAS1 provide a model for enzyme activation, but they
do not explain how multiple OAS domains discriminate RNA length. Here, we discover that human OAS2 ex-
ists in an auto-inhibited state as a zinc-mediated dimer and present a mechanism for RNA length discrimina-
tion: the catalytically deficient domain acts as a molecular ruler that prevents autoreactivity to short RNAs.
We demonstrate that dimerization and myristoylation localize OAS2 to Golgi membranes and that this is
required for OAS2 activation and the restriction of viruses that exploit the endomembrane system for repli-
cation, e.g., coronaviruses. Finally, our results highlight the non-redundant role of OAS proteins and empha-
size the clinical relevance of OAS2 by identifying a patient with a loss-of-function mutation associated with
autoimmune disease.

This work has been published in the journal in Molecular Cell.