Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

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dc.contributor.authorYu, Corey H.
dc.contributor.authorBhattacharya, Akash
dc.contributor.authorPersaud, Mirjana
dc.contributor.authorTaylor, Alexander B.
dc.contributor.authorWang, Zhonghua
dc.contributor.authorBulnes-Ramos, Angel
dc.contributor.authorXu, Joella
dc.contributor.authorSelyutina, Anastasia
dc.contributor.authorMartinez-Lopez, Alicia
dc.contributor.authorCano, Kristin
dc.contributor.authorDemeler, Borries
dc.contributor.authorKim, Baek
dc.contributor.authorHardies, Stephen C.
dc.contributor.authorDiaz-Griffero, Felipe
dc.contributor.authorIvanov, Dmitri N.
dc.date.accessioned2021-06-24T22:09:48Z
dc.date.available2021-06-24T22:09:48Z
dc.date.issued2021
dc.descriptionOpen access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesen_US
dc.description.abstractSAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein—dephosphorylation of deoxynucleotide triphosphates (dNTPs)—implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3’ to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationYu, C. H., Bhattacharya, A., Persaud, M., Taylor, A. B., Wang, Z., Bulnes-Ramos, A., Xu, J., Selyutina, A., Martinez-Lopez, A., Cano, K., Demeler, B., Kim, B., Hardies, S. C., Diaz-Griffero, F., & Ivanov, D. N. (2021). Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification. Nature Communications, 12, Article: 731 (2021). https://doi.org/10.1038/s41467-021-21023-8en_US
dc.identifier.urihttps://hdl.handle.net/10133/5918
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUT Health San Antonioen_US
dc.publisher.institutionAlbert Einstein College of Medicineen_US
dc.publisher.institutionEmory School of Medicineen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.institutionUniversity of Montanaen_US
dc.publisher.urlhttps://doi.org/10.1038/s41467-021-21023-8en_US
dc.subjectMedical researchen_US
dc.subjectStructural biologyen_US
dc.subjectNucleic acid binding
dc.subjectSAMHD1
dc.subjectAntiretroviral
dc.subject.lcshX-ray crystallography
dc.subject.lcshMedicine--Research
dc.titleNucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modificationen_US
dc.typeArticleen_US
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