High-resolution structure of RNA G-quadruplex containing unique structural motifs originating from the 5′-UTR of human tyrosine kinase 2 (TYK2)

Orehova, Maria (author), Plavec, Janez (author), Kocman, Vojč (author)

Tyrosine kinase 2 (TYK2) is a member of the JAK family of nonreceptor-associated tyrosine kinases together with highly homologous JAK1, JAK2, and JAK3 paralogues. Overexpression of TYK2 is associated with several inflammatory diseases, including severe complications during the COVID-19 infection. Since the downregulation of JAK paralogues could lead to serious health consequences or even death, it is critical to avoid it when designing drugs to suppress TYK2. To achieve the required specificity only for TYK2, researchers have recently selectively targeted TYK2 mRNA by developing antisense oligonucleotides. In this work, we expand the target space of TYK2 mRNA by showing that the mRNA adopts tetra-helical noncanonical structures called G-quadruplexes. We identified a TYKwt RNA oligonucleotide from the 5′-UTR of TYK2 mRNA, which adopts multiple different parallel G-quadruplexes that exist at equilibrium. Using NMR spectroscopy, we showed that some of the G-quadruplexes adopt unique structural motifs, mainly due to the formation of a stable GA bulge. Using guanine to uridine substitutions, we prepared the oligonucleotide TYK3_U6, which serves as an excellent model for the bulged G-quadruplexes formed by the TYKwt oligonucleotide. NMR structural analysis, including data on the residual coupling constants (RDC) of the loop regions, unveiled that the studied three-quartet parallel G-quadruplex contains many unusual structural features such as a G(U)A bulge, a guanine residue in the syn conformation, A and U residues stacked on the top G-quartet, and a well-defined adenine from a three-residue long propeller loop oriented in the groove, all of which could be valuable targets for future drug design.

• Language: English
• Keywords: biopolymers, chemical structure, G-quadruplex, genetics, guanine
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 7215–7229
• Numbering: Vol. 9, iss. 6
• PID: 20.500.12556/RUL-156059
• UDC: 577
• ISSN on article: 2470-1343
• DOI: 10.1021/acsomega.3c09592
• COBISS.SI-ID: 189432835
• Publication date in RUL: 06.05.2024

Record is a part of a journal

• Title: ACS omega
• Shortened title: ACS omega
• Publisher: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: biokemija, g-kvadrupleksi, spektroskopija, NMR, vnetja, bolezni, COVID-19

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0242
• Name: Kemija in struktura bioloških učinkovin

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: Z1-3192
• Name: Strukturna in dinamična karakterizacija mitohondrijskih transportnih RNA (mt-tRNA) in njihovih fragmentov