Structural insights into how metallochaperones UreE and UreG interact to deliver a toxic metal to urease.

September 8, 2026| Source: Proceedings of the National Academy of Sciences of the United States of America

Maturation of urease, a virulence factor for Helicobacter pylori infection, requires the delivery of nickel ions to the metalloenzyme. To avoid cytotoxicity, Ni(II) ions are transferred within protein complexes of metallochaperones to ensure that the toxic metal does not escape into the cytoplasm. In the urease maturation pathway, metallochaperone UreG receives its Ni(II) ions by forming a 2:2 complex with another metallochaperone UreE. Using C-terminal truncation variants of UreE [UreE(1-158) and UreE(1-148)], we determined the crystal structures of the UreE 2 G 2 complex bound with Ni(II) ions and GMPPNP, a nonhydrolyzable GTP analogue. UreE-UreG interactions are asymmetric, with the UreG dimer interacting mainly with the proximal UreE (closest to UreG). GTP binding induces conformational changes in the residues Asp37-Asp43 and the CPH motif (Cys66-Pro67-His68) of distal UreG that enable its anchorage to the UreE 2 G 2 complex. His68 of distal UreG moves toward and chelates a Ni(II) ion at the UreE binding site. Formation of the UreE 2 G 2 complex juxtaposes the Ni(II) binding sites of UreE and UreG. Supported by in vitro binding analyses, structural comparison suggests that nickel transfer from UreE to UreG induces conformational changes that weaken UreE-UreG interactions, thereby providing a mechanism for the dissociation of Ni(II)-bound UreG from the UreE 2 G 2 complex. Our work presents a paradigm on how GTP and Ni(II) binding allosterically regulate the formation of a metallochaperone complex to facilitate nickel transfer.

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