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Cited by 90Trace Elements in HealthHeavy Metal Exposure and ToxicityIron Metabolism and Disorders

Protein metalation in biology

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Foster, Andrew W., Young, Tessa R., Chivers, Peter T., Robinson, Nigel J.·2022·Current Opinion in Chemical Biology
DOI 10.1016/j.cbpa.2021.102095PMC PMC8867077
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Abstract

Inorganic metals supplement the chemical repertoire of organic molecules, especially proteins. This requires the correct metals to associate with proteins at metalation. Protein mismetalation typically occurs when excesses of unbound metals compete for a binding site ex vivo. However, in biology, excesses of metal-binding sites typically compete for limiting amounts of exchangeable metals. Here, we summarise mechanisms of metal homeostasis that sustain optimal metal availabilities in biology. We describe recent progress to understand metalation by comparing the strength of metal binding to a protein versus the strength of binding to competing sites inside cells.

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  • Zn2+ and Cu+ have a high affinity for ligands, with small labile pools and no free, fully hydrated ions at equilibrium.

    “Zn2+ and Cu+ have a high affinity for ligands, with small labile pools and no free, fully hydrated ions at equilibrium.3,12”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [3]

    The Mismetalation section says Cu+ forms exceptionally tight complexes, and the Associative metalation and available metal section describes extensive Zn2+ binding and a negligible source of unbound Zn2+. The paper does not establish that both metals have small labile pools or that neither has any fully hydrated ions at equilibrium; it discusses an extremely low, rather than strictly zero, availability of hydrated Zn2+. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The metal ions relevant to biology span from highly available, with substantial pools of free ions (K+ and Mg2+), to those that have an average of less than one free ion per bacterial cell (Zn2+ and Cu+).

    “The metal ions relevant to biology have properties that span the range from highly available, with substantial pools of free ions (K+ and Mg2+), to those that have an average of less than one free ion per bacterial cell (Zn2+ and Cu+).3,20”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [3]

    The section “Intracellular metal availability follows the inverse of the Irving–Williams series” describes a range of free-metal concentrations, and “Associative metalation and available metal” says free Zn²⁺ is so scarce that it is fleetingly available in roughly one cell in a million. Our copy does not establish substantial free K⁺ and Mg²⁺ pools or quantify free Cu⁺ as averaging less than one ion per bacterial cell. No page numbers are available in the indexed copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • For Zn2+ and Cu+, the notional free metal pool is less than one atom per cell at equilibrium, and metal mobility relies on ligand exchange chemistry.

    “For Zn2+ and Cu+, however, the notional free metal pool is less than one atom per cell at equilibrium, and the mobility of metals relies on ligand exchange chemistry.3,31,32”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [3]

    In “Associative metalation and available metal” (page unavailable), the paper says that femtomolar Zn2+ availability corresponds to far less than one atom per E. coli cell volume, and it describes Cu+ transfer by ligand exchange. It does not give a corresponding per-cell calculation for free Cu+, and it presents ligand exchange as a route for metalation rather than establishing that all metal mobility relies on it. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Metalloregulator or riboswitch sensitivity corresponds to a nominal concentration of free aquated ions calculated from the free energy change for the metal binding affinity needed to effect changes in gene expression.

    “Their sensitivity corresponds to a nominal concentration of free (aquated) ions (right axis) as calculated from the free energy change (ΔG, left axis) for the metal binding affinity needed to effect changes in gene expression.3”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [3]

  • Labile cation pools are sensed by metalloregulatory systems and serve to metalate nascent metalloproteins.

    “The labile cation pools are sensed by metalloregulatory systems1,219 and serve to metalate nascent metalloproteins.3”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [3]

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Cited by

Sorted by citations

Authors
Foster, A. W., Young, T. R., Chivers, P. T., & Robinson, N. J.
Affiliations
Durham University (GB)
Corresponding author
Robinson, Nigel J.
ORCID
Venue
Current Opinion in Chemical Biology
Publisher
Elsevier BV
Published
2022-02
Volume
66
Pages
102095
ISSN
1367-5931 (ISSN-L)
DOI
10.1016/j.cbpa.2021.102095
PMC
PMC8867077
OpenAlex
W3211677758
Cited by
90
References
6
Citations by year
2026: 17 · 2025: 14 · 2024: 25 · 2023: 17 · 2022: 16
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Chemical Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Durham Research Online (Durham University) (acceptedVersion, other-oa)
  • Durham Research Online (Durham University) (submittedVersion, cc-by)
Funders
Biotechnology and Biological Sciences Research Council (BB/V006002/1, BB/S009787/1, BB/R002118/1)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords
metal homeostasis, metal binding affinity, metal binding sites, metal competition, exchangeable metals, metalloproteins
MeSH terms
Biology, Cobalt, Copper, Manganese, Metals, Zinc

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