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@ARTICLE{Merold:279044,
author = {Merold, Veronika and Bekere, Indra and Kretschmer, Stefanie
and Schnell, Adrian F and Kmiec, Dorota and Sivarajan, Rinu
and Lammens, Katja and Liu, Rou and Mergner, Julia and
Teppert, Julia and Hirschenberger, Maximilian and Henrici,
Alexander and Hammes, Sarah and Buder, Kathrin and Weitz,
Marcus and Hackmann, Karl and Koenig, Lars M and Pichlmair,
Andreas and Schwierz, Nadine and Sparrer, Konstantin M J and
Lee-Kirsch, Min Ae and de Oliveira Mann, Carina C},
title = {{S}tructural basis for {OAS}2 regulation and its antiviral
function.},
journal = {Molecular cell},
volume = {85},
number = {11},
issn = {1097-2765},
address = {[Cambridge, Mass.]},
publisher = {Cell Press},
reportid = {DZNE-2025-00674},
pages = {2176 - 2193.e13},
year = {2025},
abstract = {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'-oligoadenylates 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
exists in an auto-inhibited state as a zinc-mediated dimer
and present a mechanism for RNA length discrimination: 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 replication, e.g., coronaviruses. Finally, our
results highlight the non-redundant role of OAS proteins and
emphasize the clinical relevance of OAS2 by identifying a
patient with a loss-of-function mutation associated with
autoimmune disease.},
keywords = {2',5'-Oligoadenylate Synthetase: genetics /
2',5'-Oligoadenylate Synthetase: chemistry /
2',5'-Oligoadenylate Synthetase: metabolism / Humans / Golgi
Apparatus: enzymology / Golgi Apparatus: virology / Protein
Multimerization / HEK293 Cells / Virus Replication /
Mutation / RNA, Double-Stranded: metabolism / RNA,
Double-Stranded: genetics / HeLa Cells / Endoribonucleases:
metabolism / Endoribonucleases: genetics /
Structure-Activity Relationship / Adenine Nucleotides /
Oligoribonucleotides / OAS2 (Other) / RNA sensing (Other) /
RNase L (Other) / innate immunity (Other) / localization
(Other) / oligoadenylates (Other) / structural biology
(Other) / virus restriction (Other) / 2',5'-Oligoadenylate
Synthetase (NLM Chemicals) / OAS2 protein, human (NLM
Chemicals) / 2',5'-oligoadenylate (NLM Chemicals) / RNA,
Double-Stranded (NLM Chemicals) / 2-5A-dependent
ribonuclease (NLM Chemicals) / Endoribonucleases (NLM
Chemicals) / Adenine Nucleotides (NLM Chemicals) /
Oligoribonucleotides (NLM Chemicals)},
cin = {AG Sparrer},
ddc = {610},
cid = {I:(DE-2719)1910003},
pnm = {351 - Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40412389},
doi = {10.1016/j.molcel.2025.05.001},
url = {https://pub.dzne.de/record/279044},
}