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Merold, V.* ; Bekere, I.* ; Kretschmer, S.* ; Schnell, A.F.* ; Kmiec, D.* ; Sivarajan, R.* ; Lammens, K.* ; Liu, R.* ; Mergner, J.* ; Teppert, J.* ; Hirschenberger, M.* ; Henrici, A.* ; Hammes, S.* ; Buder, K.* ; Weitz, M.* ; Hackmann, K.* ; Koenig, L.M.* ; Pichlmair, A. ; Schwierz, N.* ; Sparrer, K.M.J.* ; Lee-Kirsch, M.A.* ; de Oliveira Mann, C.C.*

Structural basis for OAS2 regulation and its antiviral function.

Mol. Cell 85, 2176-2193.e13 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Oas2 ; Rna Sensing ; Rnase L ; Innate Immunity ; Localization ; Oligoadenylates ; Structural Biology ; Virus Restriction; Double-stranded-rna; 2'-5' Oligoadenylate Synthetase; Interferon-inducible Enzymes; Multiple Sequence Alignment; Protein-synthesis; 2',5'-oligoadenylate Synthetase; 2'-5'-oligoadenylate Synthetase; Molecular-dynamics; 2-5a Synthetase; 100-kda Forms
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Zeitschrift Molecular Cell
Quellenangaben Band: 85, Heft: 11, Seiten: 2176-2193.e13 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen Sachbeihilfe grant
German Research Foundation Emmy Nother Program
European Research Council
German Federal Ministry of Education and Research (BMBF)

German Research Foundation
Baustein grant of the Medical Faculty, Ulm University
DFG Walter Benjamin Fellowship
Baden-Wurttemberg Stiftung (AutophagyBoost)
Erlangen National High-Performance Computing Center (NHR@FAU) of the Friedrich-Alexander-Universitat Erlangen-Nurnberg under the NHR project