Ca
            <sup>2+</sup>
            Binding in Proteins of the Calmodulin Superfamily: Cooperativity, Electrostatic Contributions and Molecular Mechanisms

Forsén, Sture; Linse, Sara; Drakenberg, Torbjörn; Kördel, Johan; Akke, Mikael; Sellers, Peter; Johansson, Charlotta; Thulin, Eva; Андерссон, И.; Brodin, Peter

doi:10.1002/9780470514146.ch14

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…Conversely, Ca 2+ first occupies the higher affinity C-terminal domain EF-hand sites in CaM, followed by occupancy of the N-terminal domain sites [63]. Additionally, binding of Ca 2+ in each domain involves cooperativity between the paired EF-Hand sites [64, 65] which is believed to be due to the formation of a short β-sheet between residues in position 8 of the paired EF-Loops joining EF-I with EF-II, and EF-III with EF-IV [66, 67]. Loss of cooperativity between the EF-Hand pairs, as suggested by structural differences between the two metals, would provide a plausible explanation for the similar affinities between Pb 2+ and the four EF-Hand sites in CaM.…”

Section: Discussionmentioning

confidence: 99%

“…6), while residues in sites EF-III and EF-IV appear unperturbed. These data suggest that Pb 2+ displaces Ca 2+ only in the N-terminal domain sites EF-I and EF-II, and we can speculate that the positive cooperativity associated with Ca 2+ -binding between the paired sites EF-III and EF-IV [64, 65] in the C-terminal domain is sufficient to inhibit translocation of Pb 2+ into the sites, while the 8-fold higher affinity of CaM for Pb 2+ compared with Ca 2+ in the N-terminal domain is sufficient for Pb 2+ to displace Ca 2+ .…”

Section: Discussionmentioning

confidence: 99%

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Metal toxicity and opportunistic binding of Pb2+ in proteins

Kirberger

Wong

Jiang

et al. 2013

Journal of Inorganic Biochemistry

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Lead toxicity is associated with various human diseases. While Ca2+ binding proteins such as calmodulin (CaM) are often reported to be molecular targets for Pb2+-binding and lead toxicity, the effect of Pb2+ on the Ca2+/CaM regulated biological activities cannot be described by the primary mechanism of ionic displacement (e.g., ionic mimicry). The focus of this study was to investigate the mechanism of lead toxicity through binding differences between Ca2+ and Pb2+ for CaM, an essential intracellular trigger protein with two EF-Hand Ca2+-binding sites in each of its two domains that regulates many molecular targets via Ca2+-induced conformational change. Fluorescence changes in phenylalanine indicated that Pb2+ binds with 8-fold higher affinity than Ca2+ in the N-terminal domain. Additionally, NMR chemical shift changes and an unusual biphasic response observed in tyrosine fluorescence associated with C-terminal domain sites EF-III and EF-IV suggest a single higher affinity Pb2+-binding site with a 3-fold higher affinity than Ca2+, coupled with a second site exhibiting affinity nearly equivalent to that of the N-terminal domain sites. Our results further indicate that Pb2+ displaces Ca2+ only in the N-terminal domain, with minimal perturbation of the C-terminal domain, however significant structural/dynamic changes are observed in the trans-domain linker region which appear to be due to Pb2+-binding outside of the known calcium-binding sites. These data suggest that opportunistic Pb2+-binding in Ca2+/CaM has a profound impact on the conformation and dynamics of the essential molecular recognition sites of the central helix, and provides insight into the molecular toxicity of non-essential metal ions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metal toxicity and opportunistic binding of Pb2+ in proteins

Kirberger

Wong

Jiang

et al. 2013

Journal of Inorganic Biochemistry

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“…It also contributes to the fine-tuning of the Ca 2C -binding affinity and cooperativity. 24,26 By combining EFhand motifs having different characteristics, domains with highly specialized conformational response and target specificity have evolved. The diversity of structural forms in EF-hand proteins is greatly expanded by the various types of domaindomain interactions (for a review, see Nelson & Chazin 12 ).…”

Section: The Two-ef-hand Domain As a Functional Unitmentioning

confidence: 99%

“…22 Evenas et al 23 published an overview of the intra-and extra-cellular Ca 2C -signaling from the structural perspective. There are several reviews focused on the Ca 2C -binding properties of the EF-hand proteins, [24][25][26][27][28] and on the target binding mechanisms. [29][30][31][32][33][34][35] A selection of articles covering broad aspects of Ca 2C -signaling can be found in the book edited by Ernesto Carafoli & Claude Klee.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for Diversity of the EF-hand Calcium-binding Proteins

Grabarek

2006

Journal of Molecular Biology

343

370

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“…Moreover, cooperativity may occur both within and between domains. For example, each of the paired EF-hands in the respective N- and C-terminal domains of CaM appear to bind Ca 2+ ions cooperatively (127), but further evidence suggests that the domains bind cooperatively, as well, so that Ca 2+ occupies both EF-hand sites in the higher affinity C-terminal domain sites first, which produces minor conformational changes that enhance binding in the EF-hand sites in the N-terminal domain (128). These cooperative effects appear to be of critical importance for producing conformational changes in responses to fluctuations in Ca 2+ concentrations (129), which would directly affect Ca 2+ signal transduction.…”

Section: Nmr/binding Studiesmentioning

confidence: 99%

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

et al. 2016

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Metal ions play crucial roles in numerous biological processes, facilitating biochemical reactions by binding to various proteins. An increasing body of evidence suggests that neurotoxicity associated with exposure to nonessential metals (e.g., Pb2+) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb2+ to interfere with Zn2+ and Ca2+-dependent functions. However, the molecular mechanism behind Pb2+ toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca2+ binding protein (CaBP) targets for Pb2+ such as calmodulin (CaM), synaptotagmin, neuronal calcium sensor-1 (NCS-1), N-methyl-D-aspartate receptor (NMDAR) and family C of G-protein coupled receptors (cGPCRs), and their involvement in Ca2+-signalling pathways. We then compare metal binding properties between Ca2+ and Pb2+ to understand the structural implications of Pb2+ binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb2+ binding are discussed to investigate the molecular mechanism behind Pb2+ toxicity. These studies identify an opportunistic, allosteric binding of Pb2+ with CaM that is distinct from ionic displacement. Together, this data suggests three potential modes of Pb2+ activity related to molecular and/or neural toxicity: (i) Pb2+ can occupy Ca2+-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb2+ can mimic Ca2+ in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb2+ binds outside of the Ca2+-binding sites, resulting in allosteric modulation of the proteins activity. Moreover, the data further suggest that even low concentrations of Pb2+ can interfere at multiple points within the neuronal Ca2+ signalling pathways to cause neurotoxicity.

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Ca ²⁺ Binding in Proteins of the Calmodulin Superfamily: Cooperativity, Electrostatic Contributions and Molecular Mechanisms

Cited by 9 publications

References 33 publications

Metal toxicity and opportunistic binding of Pb2+ in proteins

Metal toxicity and opportunistic binding of Pb2+ in proteins

Structural Basis for Diversity of the EF-hand Calcium-binding Proteins

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

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Ca 2+ Binding in Proteins of the Calmodulin Superfamily: Cooperativity, Electrostatic Contributions and Molecular Mechanisms

Cited by 9 publications

References 33 publications

Metal toxicity and opportunistic binding of Pb2+ in proteins

Metal toxicity and opportunistic binding of Pb2+ in proteins

Structural Basis for Diversity of the EF-hand Calcium-binding Proteins

Defining potential roles of Pb2+in neurotoxicity from a calciomics approach

Contact Info

Product

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Ca ²⁺ Binding in Proteins of the Calmodulin Superfamily: Cooperativity, Electrostatic Contributions and Molecular Mechanisms

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach