Structural Analysis of Uranyl Complexation by the EF‐Hand Motif of Calmodulin: Effect of Phosphorylation

Sauge‐Merle, Sandrine; Brulfert, Florian; Pardoux, Romain; Solari, Pier Lorenzo; Lemaire, David; Safi, Samir; Guilbaud, Philippe; Simoni, E.; Merroun, Mohamed L.; Berthomieu, Catherine

doi:10.1002/chem.201703484

Cited by 19 publications

(48 citation statements)

References 72 publications

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“…As shown by Berthomieu and co-workers [64], the phosphorylation of Thr at position 9 in the site 1 EF-hand motif of CaM, together with introduction of a Tyr at position 7, increased the binding affinity of uranyl by a factor of~5 (K D decreased from 25 to 5 nM) at pH 6, and by two orders of magnitude (K D = 0.25 nM) at pH 7. The direct involvement of phosphothreonine in uranyl coordination by a monodentate phosphoryl group was further confirmed by FTIR difference spectra and EXAFS data [66]. These observations suggest a crucial role for the phosphoryl group in enhancing the uranyl binding affinity of phosphorylated proteins at physiological pH.…”

Section: Binding To Native Metal-binding Sitesmentioning

confidence: 59%

Uranyl Binding to Proteins and Structural-Functional Impacts

Lin

2020

Biomolecules

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The widespread use of uranium for civilian purposes causes a worldwide concern of its threat to human health due to the long-lived radioactivity of uranium and the high toxicity of uranyl ion (UO 2 2+ ). Although uranyl-protein/DNA interactions have been known for decades, fewer advances are made in understanding their structural-functional impacts. Instead of focusing only on the structural information, this article aims to review the recent advances in understanding the binding of uranyl to proteins in either potential, native, or artificial metal-binding sites, and the structural-functional impacts of uranyl-protein interactions, such as inducing conformational changes and disrupting protein-protein/DNA/ligand interactions. Photo-induced protein/DNA cleavages, as well as other impacts, are also highlighted. These advances shed light on the structure-function relationship of proteins, especially for metalloproteins, as impacted by uranyl-protein interactions. It is desired to seek approaches for biological remediation of uranyl ions, and ultimately make a full use of the double-edged sword of uranium.Proteins, especially for metalloproteins, play vital roles in supporting life, including electron-transfer, O 2 -binding and delivery, and catalysis, etc [11][12][13][14][15][16][17][18]. To date, a plenitude of proteins have been shown to interact with UO 2 2+ , such as proteins in blood (human serum albumin, HSA; transferrin, Tf;hemoglobin, Hb), proteins involved in bone growth (osteopontin, OPN; fetuin-A), and the intracellar proteins (metallothionein, MT; cytochromes b 5 /c; Cyt b 5 /c; calmodulin, CaM), etc [19]. Although the structural features of some uranyl-protein complexes are well-documented [7-9], fewer advances are made in understanding the functional impacts of uranyl-protein interactions, with much less for other actinides-proteins interactions, as reviewed by Creff et al. very recently [20]. Instead of focusing only on the structural information, this review highlights the recent advances in understanding the binding of uranyl to proteins, as illustrated in Scheme 1, in either potential, native or artificial metal-binding sites, or the corresponding structural-functional impacts, such as inducing conformational changes and disrupting protein-protein/DNA/ligand interactions. Future directions for studying uranyl-protein interactions are also prospected.

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Section: Binding To Native Metal-binding Sitesmentioning

confidence: 59%

Uranyl Binding to Proteins and Structural-Functional Impacts

Lin

2020

Biomolecules

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“…Phospho-T-CaM diminishes SK channel conductance [66]. HypertensionGQNP T 44 EAELAffect EF-hand II In vivo KMKD T 79 DSEEAffect flexible central linkerKDTD S 81 EEEIAffect flexible central linker In vitro Phospho-T 29 -CaM enhances uranium binding [75,76]. Cell toxicityNGYI S 101 AAELAffect EF-hand IIICaMK-IV In vitro Phospho-T 44 -CaM, phosphorylated by CaMK-IV, inhibits CaMK-II [68]GEKL T 117 DEEVAffect EF-hand IVPKCα In vitro Melatonin enhances phospho-S/T-CaM levels [72].…”

Section: Phospho-tyr-cam In Pathophysiologymentioning

confidence: 99%

“…Uranium chemical toxicity in living organisms is due, in part, to the interaction of the uranyl ion with cellular proteins. The first EF-hand Ca 2+ -binding motif of CaM has about thousand times more affinity for uranyl than for Ca 2+ , and in vitro studies demonstrated that phosphorylation of Arabidopsis thaliana CaM by CK2 at a threonine in the first Ca 2+ -binding loop, increases the uranyl affinity at physiological pH [75,76]. Another kinase known to phosphorylate the first EF-hand Ca 2+ -binding site of vertebrate CaM at Thr29, and in lesser extent Thr26, is MLCK [77].…”

Section: Phospho-ser/thr-cam In Pathophysiologymentioning

confidence: 99%

The multifunctional role of phospho-calmodulin in pathophysiological processes

Villalobo

2018

Biochemical Journal

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Calmodulin (CaM) is a versatile Ca2+-sensor/transducer protein that modulates hundreds of enzymes, channels, transport systems, transcription factors, adaptors and other structural proteins, controlling in this manner multiple cellular functions. In addition to its capacity to regulate target proteins in a Ca2+-dependent and Ca2+-independent manner, the posttranslational phosphorylation of CaM by diverse Ser/Thr- and Tyr-protein kinases has been recognized as an important additional manner to regulate this protein by fine-tuning its functionality. In this review, we shall cover developments done in recent years in which phospho-CaM has been implicated in signalling pathways that are relevant for the onset and progression of diverse pathophysiological processes. These include diverse systems playing a major role in carcinogenesis and tumour development, prion-induced encephalopathies and brain hypoxia, melatonin-regulated neuroendocrine disorders, hypertension, and heavy metal-induced cell toxicity.

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“…26 The highest affinity was achieved for peptide CaM-M1c (sequence in Scheme 1), which basically retains the sequence of the site I of native calmodulin (CaM-nat). The difference between CaM-M1c and CaM-nat are (1) Phe 13 and Val 29 substitutions by Cys with concomitant disulfide-bridge formation to keep the peptide in a folded state, (2) fluorescence labeling through Thr 20 Tyr mutation. Because the highest affinity was achieved for the peptide retaining its natural sequence, their attempts to engineer ''uranyl binder'' essentially failed.…”

Section: Uranyl(vi) Binding To Cyclic Peptidesmentioning

confidence: 99%