Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach

Valeyev, Najl V.; Bates, Declan G.; Heslop-Harrison, J. S.; Postlethwaite, Ian; Kotov, Nikolay V.

doi:10.1186/1752-0509-2-48

Cited by 44 publications

(49 citation statements)

References 54 publications

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“…Additionally, as previously described, the inter-hand angle (F/G, Table S3) also has a value that is intermediate between the Ca 2+ -loaded and the Ca 2+ -free forms. It has been noted that Ca 2+ binding in the C-lobe is highly co-operative (Valeyev et al, 2008). Thus, subtle changes in the Ca 2+ affinities of individual C-lobe EF hands could be amplified to a large extent.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

et al. 2016

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SUMMARY Binding of Ca2+-loaded calmodulin (CaM) activates eukaryotic elongation factor 2 kinase (eEF-2K) that phosphorylates eEF-2, its only known cellular target, leading to a decrease in global protein synthesis. Here, using an eEF-2K-derived peptide (eEF-2KCBD) that encodes the region necessary for its CaM-mediated activation, we provide a structural basis for their interaction. The striking feature of this association is the absence of Ca2+ from the CaM C-lobe sites, even under high Ca2+ conditions. eEF-2KCBD engages CaM largely through the C-lobe of the latter in an anti-parallel 1-5-8 hydrophobic mode reinforced by a pair of unique electrostatic contacts. Sparse interactions of eEF-2KCBD with the CaM N-lobe results in persisting inter-lobe mobility. A conserved eEF-2K residue (W85) anchors it to CaM by inserting into a deep hydrophobic cavity within the CaM C-lobe. Mutation of this residue (W85S) substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells.

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Section: Discussionmentioning

confidence: 99%

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

et al. 2016

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“…For protein complexes to perform their biological functions, a trade‐off between structural preorganization and conformational flexibility (compliance) is often required. For instance, to accommodate structurally diverse ligands (induced fit), the interface regions of complexes with broad selectivity profiles require a substantial degree of conformational flexibility; calmodulin is one example of such a structurally adaptable molecular template . The interfacial SP in such proteins, although limited in size, may facilitate the formation of the complex by restricting the degree of conformational freedom and nucleating induced fit by promoting directional conformational changes, thereby mitigating the entropy debt.…”

Section: Introductionmentioning

confidence: 99%

The role of protein “Stability patches” in molecular recognition: A case study of the human growth hormone‐receptor complex

2015

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Dynamic characteristics of protein surfaces are among the factors determining their functional properties, including their potential participation in protein-protein interactions. The presence of clusters of static residues-"stability patches" (SPs)-is a characteristic of protein surfaces involved in intermolecular recognition. The mechanism, by with SPs facilitate molecular recognition, however, remains unclear. Analyzing the surface dynamic properties of the growth hormone and of its high-affinity variant we demonstrated that reshaping of the SPs landscape may be among the factors accountable for the improved affinity of this variant to the receptor. We hypothesized that SPs facilitate molecular recognition by moderating the conformational entropy of the unbound state, diminishing enthalpy-entropy compensation upon binding, and by augmenting the favorable entropy of desolvation. SPs mapping emerges as a valuable tool for investigating the structural basis of the stability of protein complexes and for rationalizing experimental approaches, such as affinity maturation, aimed at improving it.

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“…[5][6][7] Switchable proteins with new functionalities can be created through protein engineering aer understanding their switching mechanisms. [10][11][12][13][14][15] A wild type (WT) calbindin-D 9k , being a small globular protein of the calmodulin superfamily and possessing a pair of helix-loop-helix structures called EF-hand (Lys1-Gln75), plays a key role in calcium binding and calcium buffer regulations as a typical functional unit. [10][11][12][13][14][15] A wild type (WT) calbindin-D 9k , being a small globular protein of the calmodulin superfamily and possessing a pair of helix-loop-helix structures called EF-hand (Lys1-Gln75), plays a key role in calcium binding and calcium buffer regulations as a typical functional unit.…”

Section: Introductionmentioning

confidence: 99%

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study

Tong

Wang

et al. 2015

RSC Adv.

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We carried out conventional molecular dynamics simulations, targeted molecular dynamics simulations and energy calculations for the two states (AFF-D 9k -N 0 and AFF-D 9k -N) of the alternate frame folding (AFF) calbindin-D 9k protein and their conformational transition in the Ca 2+ -free form to address the dynamical transition mechanism from AFF-D 9k -N 0 to AFF-D 9k -N states. We found that the structural characteristics of the two stable AFF-D 9k -N 0 and AFF-D 9k -N states present the coupled conformations of mutually exclusive folding. The transition from AFF-D 9k -N 0 to AFF-D 9k -N states may occur via two transition states and an intermediate with the first rate-controlling barrier of 4.7 kcal mol À1 and the second barrier of 1.7 kcal mol À1 . These results showed that the conformational transition pathway from AFF-D 9k -N 0 to AFF-D 9k -N is energetically feasible due to the low rate-controlling barrier. Moreover, the stabilities of the AFF-D 9k -N 0 and AFF-D 9k -N conformations calculated by the MM_PBSA method are consistent with the available experimental result. The transition mechanism involves the relative movements of the two mutually exclusive folding regions, EF2 and EF2 0 , and their coupled folding-unfolding. The crucial mediation of the deformation of EF1 hand located at the middle of the AFF calbindin-D 9k protein plays a key role in this transition process. The correlation analysis revealed the allosteric communications between the EF2 0 and EF2 regions via the mediation of the EF1 hand during the transition of AFF-D 9k -N 0 to AFF-D 9k -N. Fig. 6 The calculated residue B-factors of (a) AFF-D 9k -N (red) and (b) AFF-D 9k -N 0 (blue) in comparison with the experimental B-factors of the crystal calbindin-D 9k protein (black), respectively. The peaks with the number of residues at the loop regions are marked in grey.This journal is

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Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach

Cited by 44 publications

References 54 publications

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

The role of protein “Stability patches” in molecular recognition: A case study of the human growth hormone‐receptor complex

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study

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Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach

Cited by 44 publications

References 54 publications

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

The role of protein “Stability patches” in molecular recognition: A case study of the human growth hormone‐receptor complex

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D9kprotein: a theoretical study

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Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study