Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion

Brayshaw, Lewis L.; Smith, R; Badaoui, Magd; Irving, James A.; Price, Stephen R.

doi:10.1039/c8mt00317c

Cited by 26 publications

(34 citation statements)

References 55 publications

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“…Upon concluding that the proteins were not obtainable in a Ca 2+ -free form without the addition of EDTA or EGTA, we decided to indirectly estimate the affinity of the proteins to Ca 2+ by measuring the binding of terbium(III) ions (Tb 3+ ), as Ca 2+ -binding proteins can also bind lanthanide ions due to similar effective ionic radii and positive charges of Ca 2+ and lanthanide ions 39 . The binding of lanthanide ions by Ca 2+ -binding proteins is usually stronger than the binding of Ca 2+ , due mainly to a higher positive charge 40 – 42 . Therefore, protein-bound Ca 2+ should be substituted by Tb 3+ .…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

Hołubowicz

Ożyhar

Dobryszycki

2021

Sci Rep

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The C1q superfamily includes proteins involved in innate immunity, insulin sensitivity, biomineralization and more. Among these proteins is otolin-1, which is a collagen-like protein that forms a scaffold for the biomineralization of inner ear stones in vertebrates. The globular C1q-like domain (gC1q), which is the most conserved part of otolin-1, binds Ca2+ and stabilizes its collagen-like triple helix. The molecular details of the assembly of gC1q otolin-1 trimers are not known. Here, we substituted putative Ca2+-binding acidic residues of gC1q otolin-1 with alanine to analyse how alanine influences the formation of gC1q trimers. We used human and zebrafish gC1q otolin-1 to assess how evolutionary changes affected the function of the protein. Surprisingly, the mutated forms of gC1q otolin-1 trimerized even in the absence of Ca2+, although they were less stable than native proteins saturated with Ca2+. We also found that the zebrafish gC1q domain was less stable than the human homologue under all tested conditions and became stabilized at higher concentrations of Ca2+, which showed that specific interactions leading to the neutralization of the negative charge at the axis of a gC1q trimer by Ca2+ are required for the trimers to form. Moreover, human gC1q otolin-1 seems to be optimized to function at lower concentrations of Ca2+, which is consistent with reported Ca2+ concentrations in the endolymphs of fish and mammals. Our results allow us to explain the molecular mechanism of assembly of proteins from the C1q superfamily, the modulating role of Ca2+ and expand the knowledge of biomineralization of vertebrate inner ear stones: otoliths and otoconia.

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Section: Resultsmentioning

confidence: 99%

Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

Hołubowicz

Ożyhar

Dobryszycki

2021

Sci Rep

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“…Studies have suggested positive impacts of RE provision in animal husbandry, suggesting a role for REs in higher organisms. 128 However, REs are not perfect mimics of Ca, 4 as recent studies of calmodulin 129,130 and cadherin 131 have shown, suggesting that REs may not play a general role as Ca substitutes in Ca-dependent proteins. Instead, the growth-promoting effects of REs in higher organisms might plausibly be linked to the microbiome; for example, both beneficial ( E. coli ) and pathogenic ( Pseudomonas aeruginosa ) bacteria possess PQQ-dependent dehydrogenases, and these or other enzymes might benefit from or be inhibited by REs.…”

Section: Lanthanides Beyond Bacteriamentioning

confidence: 99%

The Chemistry of Lanthanides in Biology: Recent Discoveries, Emerging Principles, and Technological Applications

2019

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The essential biological role of rare earth elements lay hidden until the discovery in 2011 that lanthanides are specifically incorporated into a bacterial methanol dehydrogenase. Only recently has this observation gone from a curiosity to a major research area, with the appreciation for the widespread nature of lanthanide-utilizing organisms in the environment and the discovery of other lanthanide-binding proteins and systems for selective uptake. While seemingly exotic at first glance, biological utilization of lanthanides is very logical from a chemical perspective. The early lanthanides (La, Ce, Pr, Nd) primarily used by biology are abundant in the environment, perform similar chemistry to other biologically useful metals and do so more efficiently due to higher Lewis acidity, and possess sufficiently distinct coordination chemistry to allow for selective uptake, trafficking, and incorporation into enzymes. Indeed, recent advances in the field illustrate clear analogies with the biological coordination chemistry of other metals, particularly CaII and FeIII, but with unique twists—including cooperative metal binding to magnify the effects of small ionic radius differences—enabling selectivity. This Outlook summarizes the recent developments in this young but rapidly expanding field and looks forward to potential future discoveries, emphasizing continuity with principles of bioinorganic chemistry established by studies of other metals. We also highlight how a more thorough understanding of the central chemical question—selective lanthanide recognition in biology—may impact the challenging problems of sensing, capture, recycling, and separations of rare earths.

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“…[12][13][14][15][16] To avoid the cytotoxicity of free metal ions, which is mainly caused by binding to endogenous metalloproteins and subsequent structure disruption, the metals are tightly complexed with multidentate ligands. [17][18][19][20] The most prominent chelators are the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetate (DOTA) and its analogs ( Fig. 1).…”

Section: Lanthanide Conjugates In Diagnostics and Therapymentioning

confidence: 99%

Lanthanide conjugates as versatile instruments for therapy and diagnostics

Herlan

Bräse

2020

Dalton Trans.

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Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion

Abstract: Substitutions with lanthanides reveal a high sensitivity of cadherin structure, dynamics and function to metal ion chemistry.

Cited by 26 publications

References 55 publications

Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

The Chemistry of Lanthanides in Biology: Recent Discoveries, Emerging Principles, and Technological Applications

Lanthanide conjugates as versatile instruments for therapy and diagnostics

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