Structural investigations on the interplay between metal ions targeting proteins involved in copper homeostasis

by Dr Vincenzo Mangini (CNR - IC)

Thursday 5 May 2022, 15:00 → 16:30 Europe/Rome

1/1-1 - Sala Congressi (Area della Ricerca di Bari)

The BioCryst group of the Institute of Crystallography of Bari is a multidisciplinary research team carrying out basic and applied research activities that range from the development of crystallographic methodologies and tools for data analysis to crystallization and structural characterization of biological macromolecules of biotechnological and biomedical interest.

In this seminar the attention will be focused on the structural investigations on the interplay between physiological and non-physiological metal ions targeting proteins involved in copper trafficking.

 Due to the delicate mechanisms in which essential metals are involved, the cell must be able to selectively uptake the ions and to keep their concentration constant. Copper (Cu) is required for maturation of cuproenzymes, cell proliferation, and angiogenesis, and its transport entails highly specific protein-protein interactions. In humans, the chaperone Atox1 mediates Cu delivery to P-type ATPases ATP7a and ATP7b (the Menkes and Wilson disease proteins, respectively), which are responsible for Cu release to the secretory pathway.1 Nevertheless, other metal ions are able to interfere with Cu exchange mechanisms.

From Atox1 crystals to structural model

Here, the interaction between Atox1 and Cu, zinc (Zn) or exogenous metal compounds, such as platinum (Pt) based drugs, has been explored. X-ray diffraction investigations have disclosed the Pt binding sites of Atox1, and shown that the metal-binding site (MBS) of the Atox1 dimer is partially occupied by a Pt ion, with Cu ions completing the site occupancy.2 Thus, the Pt ion is able to replace partially the Cu ion, leading to a disruption of the process that regulates Cu level. A further study has revealed the structural mechanisms underlying the interaction of Pt-based anticancer drugs with the Cu-mediated complex of Atox1 and the first domain of the Menkes ATPase.3 It was possible to determine the atomic structure of the heterodimer made by the two proteins in the act of interacting simultaneously with a Cu ion and the Pt drug. Our investigations demonstrated that the Pt-based drug can interfere with the rapid exchange of Cu between the two proteins, with possible consequences on the uptake, sequestration, and efflux of Pt-based drugs. Additionally, the interaction between Zn ions and Atox1 was investigated, showing, for the first time, that the protein is able to coordinate Zn through its Cu binding site4 and displaying that the Atox1 crystal structure, formed thanks to the metal, is able to preserve the dimeric form also without the metal in the MBS of the Atox1 dimer.