Structural characterization of non-Zn2+ Cation Diffusion Facilitator transporters
Transition metals (TM)(Co2+, Ni2+, Fe2+, Mn2+, etc.) play significant roles in all living organisms acting as co-factors in enzymes or as structure determinants in metalloproteins. These proteins are metallated in the cells by means of highly specific and regulated systems. Membrane transporters of the Cation Diffusion Facilitator (CDF) family are involved in this process by keeping the intracellular levels of transition metals under safe limits, to avoid mismetallation and oxidative cellular damage, both detrimental to metallo -enzymes and -proteins functions. The human homologs to CDF transporters (ZnTs 1-8) have the tetrads HD-HD and specifically regulate the Zn2+ homeostasis. However ZnT10, with a tetrad ND-HD, transports Mn2+ and several described loss of function mutations in the gene leads to altered Mn2+ homeostasis in brain and Parkinsonism. In bacteria and plants the specificity of transport is broaden to Mn2+, Fe2+, Co2+ and Ni2+ and it correlates with an increased variability of the side chains ligands observed in the tetrads. Our work is focused on dissecting the structural determinants leading to substrate specificity in this family.
Roles of Transition metal transporters in antibiotic resistance.
Antibiotic resistance is a recurrent problem found in treatments of bacterial infections. Multiple pieces of evidence gathered from several pathogens point toward a relationship between transition metal homeostasis and antibiotic response in human pathogens. We hypothesize that TM transporters play a direct role in intrinsic antibiotic resistance which can be further shared by acquired resistance mechanisms. The knowledge generated will allow the design of new strategies against bacterial infections.
Bióloga Paula Mihelj
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- MINCyT (FONCyT – PICT2015).
Publications (last 5 years)
- Abreu I, Mihelj P, Raimunda D. Transition metal transporters in rhizobia: tuning the inorganic micronutrient requirements to different living styles. Metallomics. 2019 Apr 17;11(4):735-755. doi: 10.1039/c8mt00372f. Review.
- Salusso A. and Raimunda D. Defining the roles of the Cation Diffusion Facilitators in Fe2+/Zn2+ homeostasis and establishment of their participation in virulence in Pseudomonas aeruginosa. Front. Cell. Infect. Microbiol. 2017 Mar; 7:84. doi: 10.3389/fcimb.2017.00084
- Raimunda D., Elso-Berberián G. Functional characterization of the CDF transporter SMc02724 (SmYiiP) in Sinorhizobium meliloti: Roles in manganese homeostasis and nodulation. Biochim Biophys Acta. 2014 Dec;1838(12):3203-11. doi: 10.1016/j.bbamem.2014.09.005. Epub 2014 Sep 19.
- Raimunda D.*, Long J.E.*, Padilla-Benavidez T., Sassetti C.M., Argüello J.M. Differential roles for the Co2+/Ni2+ transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence. Mol Microbiol. 2014 Jan;91(1) 185-97. * Equal contribution in this work.
- Periplasmic Cu response upon disruption of transmembrane Cu transport in Pseudomonas aeruginosa. Raimunda D., Padilla-Benavides T., Vogt S., Tomkinson K., Boutigny S., Finney L., Argüello J.M.. Metallomics. 2013. Jan;5(2)144 - 151
- A tetrahedral coordination of zinc during transmembrane transport by P-type Zn2+-ATPases. Raimunda D., Subramanian P., Stemmler T., Argüello J.M.. Biochim Biophys Acta. 2012 May;1818(5):1374-7
- Distinct functional roles of homologous Cu+ efflux ATPases in Pseudomonas aeruginosa. González-Guerrero M.*, Raimunda D.*, Cheng X., Argüello J.M.. Mol Microbiol. 2010 Dec;78(5):1246-58. * Equal contribution in this work.