9H1Z

Cryo-EM Structure of human OAS2 Dimer

Summary for 9H1Z

• Entry DOI: 10.2210/pdb9h1z/pdb
• EMDB information: 51786
• Descriptor: 2'-5'-oligoadenylate synthase 2, ZINC ION (2 entities in total)
• Functional Keywords: nucleotidyltransferase, zinc, oligoadenylate synthetase, innate immunity, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 169567.27

Authors

Merold, V.R.,Lammens, K.,de Oliveira Mann, C.C. (deposition date: 2024-10-10, release date: 2025-05-28, Last modification date: 2025-06-18)

Primary citation

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

PubMed 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.

PubMed: 40412389
DOI: 10.1016/j.molcel.2025.05.001

Experimental method

ELECTRON MICROSCOPY (3.3 Å)