Web of Science: 5 cites, Scopus: 6 cites, Google Scholar: cites,
Evolutionary trends in RNA base selectivity within the RNase A superfamily
Prats-Ejarque, Guillem (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Lu, Lu (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Salazar, V.A. (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Moussaoui, Mohammed (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Boix i Borràs, Esther (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data: 2019
Resum: There is a growing interest in the pharmaceutical industry to design novel tailored drugs for RNA targeting. The vertebrate-specific RNase A superfamily is nowadays one of the best characterized family of enzymes and comprises proteins involved in host defense with specific cytotoxic and immune-modulatory properties. We observe within the family a structural variability at the substrate-binding site associated to a diversification of biological properties. In this work, we have analyzed the enzyme specificity at the secondary base binding site. Towards this end, we have performed a kinetic characterization of the canonical RNase types together with a molecular dynamic simulation of selected representative family members. The RNases' catalytic activity and binding interactions have been compared using UpA, UpG and UpI dinucleotides. Our results highlight an evolutionary trend from lower to higher order vertebrates towards an enhanced discrimination power of selectivity for adenine respect to guanine at the secondary base binding site (B2). Interestingly, the shift from guanine to adenine preference is achieved in all the studied family members by equivalent residues through distinct interaction modes. We can identify specific polar and charged side chains that selectively interact with donor or acceptor purine groups. Overall, we observe selective bidentate polar and electrostatic interactions: Asn to N1/N6 and N6/N7 adenine groups in mammals versus Glu/Asp and Arg to N1/N2, N1/O6 and O6/N7 guanine groups in non-mammals. In addition, kinetic and molecular dynamics comparative results on UpG versus UpI emphasize the main contribution of Glu/Asp interactions to N1/N2 group for guanine selectivity in lower order vertebrates. A close inspection at the B2 binding pocket also highlights the principal contribution of the protein β6 and L4 loop regions. Significant differences in the orientation and extension of the L4 loop could explain how the same residues can participate in alternative binding modes. The analysis suggests that within the RNase A superfamily an evolution pressure has taken place at the B2 secondary binding site to provide novel substrate-recognition patterns. We are confident that a better knowledge of the enzymes' nucleotide recognition pattern would contribute to identify their physiological substrate and eventually design applied therapies to modulate their biological functions.
Ajuts: Ministerio de Economía y Competitividad SAF2015-66007P
Agència de Gestió d'Ajuts Universitaris i de Recerca 2016-PROD-00060
Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-1010
Nota: Altres ajuts: Fundació La Marató de TV3 (Marató 20180310)
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: RNase ; RNA ; Purine ; Catalysis ; Molecular dynamics ; Evolution ; RNase A superfamily
Publicat a: Frontiers in Pharmacology, Vol. 10 (October 2019) , art. 1170, ISSN 1663-9812

DOI: 10.3389/fphar.2019.01170
PMID: 31649540

17 p, 3.3 MB

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