Conformational change induced by binding of Mn2+ ions activates SloR transcription factor in Streptococcus mutans

Katarina Radman; Ivo Crnolatac; Nikola Bregović; Zoe Jelić Matošević; Pedro A Fernandes; Dalibor Merunka; Dijana Žilić; Ivo Piantanida; Ivana Leščić Ašler; Branimir Bertoša

doi:10.1016/j.ijbiomac.2024.138828

Conformational change induced by binding of Mn²⁺ ions activates SloR transcription factor in Streptococcus mutans

Int J Biol Macromol. 2024 Dec 17:138828. doi: 10.1016/j.ijbiomac.2024.138828. Online ahead of print.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. Electronic address: [email protected].
² Division of Organic Chemistry & Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia. Electronic address: [email protected].
³ Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. Electronic address: [email protected].
⁴ Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. Electronic address: [email protected].
⁵ LAQV, REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal. Electronic address: [email protected].
⁶ Division of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia. Electronic address: [email protected].
⁷ Division of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia. Electronic address: [email protected].
⁸ Division of Organic Chemistry & Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia. Electronic address: [email protected].
⁹ Division of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia. Electronic address: [email protected].
¹⁰ Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. Electronic address: [email protected].

PMID: 39701257
DOI: 10.1016/j.ijbiomac.2024.138828

Abstract

Streptococcus mutans, a bacterium commonly found in the human oral cavity, is considered the primary causative agent of dental caries. A key player in the pathophysiology of S. mutans is SloR, a 25-kDa metalloregulatory protein. SloR plays a crucial role in coordinating the uptake of essential metal ions, particularly manganese, with the transcription of the bacterium's virulence genes. To elucidate the molecular mechanism underlying the enhanced binding affinity of SloR to DNA upon Mn²⁺ ion binding, a combination of computational (QM and MD) and experimental (ITC, DSC, CD, EPR) methods have been employed. Computational simulations revealed that Mn²⁺ binding induces a conformational change of SloR, primarily affecting the positioning of its DNA-binding domains, bringing them to an appropriate position for DNA binding. Consequently, the protein's DNA binding affinity is modulated. Additionally, experimental findings indicate that the SloR monomer binds up to three Mn²⁺ ions and that the thermodynamic stability of SloR increases upon Mn²⁺ complexation. The presented computational results also suggest that Mn²⁺ binding at the primary binding sites is sufficient to trigger the observed conformational change in SloR.

Keywords: Allostery; Manganese metallosensors; Metal ion homeostasis; Transcriptional factor SloR.