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

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Title: Structural insights into how metallochaperones UreE and UreG interact to deliver a toxic metal to urease.
Authors: Chan CL; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Pang LTH; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Choi T; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Chan KC; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Tsang KL; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Lee KM; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China., Wong KB; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
Source: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2026 Sep 08; Vol. 123 (36), pp. e2535662123. Date of Electronic Publication: 2026 Sep 03.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms: Urease*/metabolism , Urease*/chemistry , Nickel*/metabolism , Nickel*/chemistry , Metallochaperones*/chemistry , Metallochaperones*/metabolism , Bacterial Proteins*/chemistry , Bacterial Proteins*/metabolism , Bacterial Proteins*/genetics , Helicobacter pylori*/metabolism , Carrier Proteins*/chemistry , Carrier Proteins*/metabolism, Guanosine Triphosphate/metabolism ; Guanosine Triphosphate/chemistry ; Protein Binding ; Models, Molecular ; Crystallography, X-Ray ; Binding Sites ; Protein Conformation ; Phosphate-Binding Proteins
Abstract: 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 UreE2G2 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 UreE2G2 complex. His68 of distal UreG moves toward and chelates a Ni(II) ion at the UreE binding site. Formation of the UreE2G2 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 UreE2G2 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.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Grant Information: 14117321 Research Grants Council, University Grants Committee (); 14117223 Research Grants Council, University Grants Committee (); C4041-18E Research Grants Council, University Grants Committee (); C4002-21-EF Research Grants Council, University Grants Committee (); C2003-22 W Research Grants Council, University Grants Committee (); AoE/M-403/16 Research Grants Council, University Grants Committee (); AoE/M-05/12 Research Grants Council, University Grants Committee ()
Contributed Indexing: Keywords: Helicobacter pylori; metallochaperone; nickel; protein interaction; urease maturation
Substance Nomenclature: EC 3.5.1.5 (Urease)
7OV03QG267 (Nickel)
0 (Metallochaperones)
0 (Bacterial Proteins)
0 (ureG protein, Bacteria)
0 (UreE protein, Bacteria)
0 (Carrier Proteins)
86-01-1 (Guanosine Triphosphate)
0 (Phosphate-Binding Proteins)
Entry Date(s): Date Created: 20260903 Date Completed: 20260903 Latest Revision: 20260910
Update Code: 20260910
PubMed Central ID: PMC13552852
DOI: 10.1073/pnas.2535662123
PMID: 42691087
Database: MEDLINE
FullText Text:
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DbLabel: MEDLINE
An: 42691087
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Structural insights into how metallochaperones UreE and UreG interact to deliver a toxic metal to urease.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Chan+CL%22">Chan CL</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Pang+LTH%22">Pang LTH</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Choi+T%22">Choi T</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Chan+KC%22">Chan KC</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Tsang+KL%22">Tsang KL</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Lee+KM%22">Lee KM</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.<br /><searchLink fieldCode="AU" term="%22Wong+KB%22">Wong KB</searchLink>; School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
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  Data: <searchLink fieldCode="JN" term="%227505876%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink> [Proc Natl Acad Sci U S A] 2026 Sep 08; Vol. 123 (36), pp. e2535662123. <i>Date of Electronic Publication: </i>2026 Sep 03.
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  Data: Journal Article
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  Data: English
– Name: TitleSource
  Label: Journal Info
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22National+Academy+of+Sciences%22">National Academy of Sciences </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>7505876 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1091-6490 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200278424%22">00278424 </searchLink><i>NLM ISO Abbreviation: </i>Proc Natl Acad Sci U S A <i>Subsets: </i>MEDLINE
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  Label: Imprint Name(s)
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  Data: <i>Original Publication</i>: Washington, DC : National Academy of Sciences
– Name: SubjectMESH
  Label: MeSH Terms
  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Urease%22">Urease*</searchLink>/<searchLink fieldCode="MM" term="%22Urease+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Urease%22">Urease*</searchLink>/<searchLink fieldCode="MM" term="%22Urease+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Nickel%22">Nickel*</searchLink>/<searchLink fieldCode="MM" term="%22Nickel+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Nickel%22">Nickel*</searchLink>/<searchLink fieldCode="MM" term="%22Nickel+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Metallochaperones%22">Metallochaperones*</searchLink>/<searchLink fieldCode="MM" term="%22Metallochaperones+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Metallochaperones%22">Metallochaperones*</searchLink>/<searchLink fieldCode="MM" term="%22Metallochaperones+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Bacterial+Proteins%22">Bacterial Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Bacterial+Proteins+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Bacterial+Proteins%22">Bacterial Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Bacterial+Proteins+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Bacterial+Proteins%22">Bacterial Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Bacterial+Proteins+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Helicobacter+pylori%22">Helicobacter pylori*</searchLink>/<searchLink fieldCode="MM" term="%22Helicobacter+pylori+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Carrier+Proteins%22">Carrier Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Carrier+Proteins+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Carrier+Proteins%22">Carrier Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Carrier+Proteins+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Guanosine+Triphosphate%22">Guanosine Triphosphate</searchLink>/<searchLink fieldCode="MH" term="%22Guanosine+Triphosphate+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Guanosine+Triphosphate%22">Guanosine Triphosphate</searchLink>/<searchLink fieldCode="MH" term="%22Guanosine+Triphosphate+chemistry%22">chemistry</searchLink> ; <searchLink fieldCode="MH" term="%22Protein+Binding%22">Protein Binding</searchLink> ; <searchLink fieldCode="MH" term="%22Models%2C+Molecular%22">Models, Molecular</searchLink> ; <searchLink fieldCode="MH" term="%22Crystallography%2C+X-Ray%22">Crystallography, X-Ray</searchLink> ; <searchLink fieldCode="MH" term="%22Binding+Sites%22">Binding Sites</searchLink> ; <searchLink fieldCode="MH" term="%22Protein+Conformation%22">Protein Conformation</searchLink> ; <searchLink fieldCode="MH" term="%22Phosphate-Binding+Proteins%22">Phosphate-Binding Proteins</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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<subscript>2</subscript>G<subscript>2</subscript> 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<subscript>2</subscript>G<subscript>2</subscript> complex. His68 of distal UreG moves toward and chelates a Ni(II) ion at the UreE binding site. Formation of the UreE<subscript>2</subscript>G<subscript>2</subscript> 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<subscript>2</subscript>G<subscript>2</subscript> 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.
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Competing interests statement:The authors declare no competing interest.
– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: 14117321 Research Grants Council, University Grants Committee (); 14117223 Research Grants Council, University Grants Committee (); C4041-18E Research Grants Council, University Grants Committee (); C4002-21-EF Research Grants Council, University Grants Committee (); C2003-22 W Research Grants Council, University Grants Committee (); AoE/M-403/16 Research Grants Council, University Grants Committee (); AoE/M-05/12 Research Grants Council, University Grants Committee ()
– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: <i>Keywords: </i>Helicobacter pylori; metallochaperone; nickel; protein interaction; urease maturation
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: EC 3.5.1.5 (Urease)<br />7OV03QG267 (Nickel)<br />0 (Metallochaperones)<br />0 (Bacterial Proteins)<br />0 (ureG protein, Bacteria)<br />0 (UreE protein, Bacteria)<br />0 (Carrier Proteins)<br />86-01-1 (Guanosine Triphosphate)<br />0 (Phosphate-Binding Proteins)
– Name: DateEntry
  Label: Entry Date(s)
  Group: Date
  Data: <i>Date Created: </i>20260903 <i>Date Completed: </i>20260903 <i>Latest Revision: </i>20260910
– Name: DateUpdate
  Label: Update Code
  Group: Date
  Data: 20260910
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  Data: PMC13552852
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  Data: 10.1073/pnas.2535662123
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  Data: 42691087
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42691087
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        Value: 10.1073/pnas.2535662123
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: e2535662123
    Subjects:
      – SubjectFull: Guanosine Triphosphate metabolism
        Type: general
      – SubjectFull: Guanosine Triphosphate chemistry
        Type: general
      – SubjectFull: Protein Binding
        Type: general
      – SubjectFull: Models, Molecular
        Type: general
      – SubjectFull: Crystallography, X-Ray
        Type: general
      – SubjectFull: Binding Sites
        Type: general
      – SubjectFull: Protein Conformation
        Type: general
      – SubjectFull: Phosphate-Binding Proteins
        Type: general
      – SubjectFull: Urease metabolism
        Type: general
      – SubjectFull: Urease chemistry
        Type: general
      – SubjectFull: Nickel metabolism
        Type: general
      – SubjectFull: Nickel chemistry
        Type: general
      – SubjectFull: Metallochaperones chemistry
        Type: general
      – SubjectFull: Metallochaperones metabolism
        Type: general
      – SubjectFull: Bacterial Proteins chemistry
        Type: general
      – SubjectFull: Bacterial Proteins metabolism
        Type: general
      – SubjectFull: Bacterial Proteins genetics
        Type: general
      – SubjectFull: Helicobacter pylori metabolism
        Type: general
      – SubjectFull: Carrier Proteins chemistry
        Type: general
      – SubjectFull: Carrier Proteins metabolism
        Type: general
    Titles:
      – TitleFull: Structural insights into how metallochaperones UreE and UreG interact to deliver a toxic metal to urease.
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              Text: 2026 Sep 08
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              Y: 2026
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