The role of conformational entropy in molecular recognition by calmodulin

Marlow, Michael S.; Dogan, Jakob; Frederick, Kendra K.; Valentine, Kathleen G.; Wand, A. Joshua

doi:10.1038/nchembio.347

Cited by 243 publications

(367 citation statements)

References 51 publications

(91 reference statements)

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“…The effects of myristoylation in hisactophilin are similar to results for other proteins where regions of increased local stability are counterbalanced by regions of decreased local stability implicated in function regulation by ligand binding (29)(30)(31). The folding energetics and mechanism for myristoylated hisactophilin support the notion that local energetic frustration and the accumulation of strain during switching can be linked to function as observed in allosteric proteins (16) and for functional and/or hydrophobic residues in other proteins (7,11,32,33).…”

Section: Discussionsupporting

confidence: 63%

Nonnative interactions regulate folding and switching of myristoylated protein

Shental-Bechor

Smith

MacKenzie

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We present an integrated experimental and computational study of the molecular mechanisms by which myristoylation affects protein folding and function, which has been little characterized to date. Myristoylation, the covalent linkage of a hydrophobic C14 fatty acyl chain to the N-terminal glycine in a protein, is a common modification that plays a critical role in vital regulated cellular processes by undergoing reversible energetic and conformational switching. Coarse-grained folding simulations for the model pH-dependent actin-and membrane-binding protein hisactophilin reveal that nonnative hydrophobic interactions of the myristoyl with the protein as well as nonnative electrostatic interactions have a pronounced effect on folding rates and thermodynamic stability. Folding measurements for hydrophobic residue mutations of hisactophilin and atomistic simulations indicate that the nonnative interactions of the myristoyl group in the folding transition state are nonspecific and robust, and so smooth the energy landscape for folding. In contrast, myristoyl interactions in the native state are highly specific and tuned for sensitive control of switching functionality. Simulations and amide hydrogen exchange measurements provide evidence for increases as well as decreases in stability localized on one side of the myristoyl binding pocket in the protein, implicating strain and altered dynamics in switching. The effects of folding and function arising from myristoylation are profoundly different from the effects of other post-translational modifications.coarse-grained simulation | funnel landscape | β-trefoil P rotein folding is governed by various physicochemical forces that bias the native state, which for many proteins is also the functional state, over the many alternative nonnative states. The network of native interactions has been found in many cases to be sufficient to capture the folding mechanism and kinetics of proteins (1, 2). The discrimination between native and nonnative interactions is the foundation of the principle of minimal frustration (3) and explains the power of native topology-based models in studying folding biophysics (4). The dominant role of native interactions is manifested by the funnel-shaped energy landscape for folding that suggests folding is robust and an efficient process. The information stored in the native topology may, however, be tuned by various factors such as confining the protein in a small space, crowding agents, or conjugating the protein to other biomolecules [e.g., oligosaccharides (5) or fatty acyl chains such as myristoyl (6)]. In addition to manipulating folding characteristics by modifications or environmental conditions, nonnative interactions, which are by definition in conflict with the native state, may decorate the folding funnel (7, 8) by increasing energetic frustration (9) between interactions and therefore landscape roughness. The degree of roughness, which affects the trapping of the protein in nonnative states, depends on the particular sequence of the pr...

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Section: Discussionsupporting

confidence: 63%

Nonnative interactions regulate folding and switching of myristoylated protein

Shental-Bechor

Smith

MacKenzie

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Although our data identify the C-terminal segment of PAPR as the primary molecular determinant for favorable binding entropy, our next goal was to better define the nature of this contribution. Total binding entropy (ΔS total ) obtained from ITC measurement of protein-protein interactions is a complex term, but can be simplified as a sum of changes in the solvation entropy (ΔS sol ), protein translational and rotational entropy (ΔS RT ) and protein conformational entropy (ΔS conf ) (28). Although accurate quantitative dissection of ΔS tot into contributions from ΔS sol , ΔS RT , and ΔS conf is difficult and often controversial, some initial insight can be obtained by combining inputs from experimental measurements and theoretical models.…”

Section: Conformational Restriction Of Oxidized Papr Is Essential Formentioning

confidence: 99%

A universal entropy-driven mechanism for thioredoxin–target recognition

Palde

Carroll

2015

Proc. Natl. Acad. Sci. U.S.A.

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Cysteine residues in cytosolic proteins are maintained in their reduced state, but can undergo oxidation owing to posttranslational modification during redox signaling or under conditions of oxidative stress. In large part, the reduction of oxidized protein cysteines is mediated by a small 12-kDa thiol oxidoreductase, thioredoxin (Trx). Trx provides reducing equivalents for central metabolic enzymes and is implicated in redox regulation of a wide number of target proteins, including transcription factors. Despite its importance in cellular redox homeostasis, the precise mechanism by which Trx recognizes target proteins, especially in the absence of any apparent signature binding sequence or motif, remains unknown. Knowledge of the forces associated with the molecular recognition that governs Trx-protein interactions is fundamental to our understanding of target specificity. To gain insight into Trx-target recognition, we have thermodynamically characterized the noncovalent interactions between Trx and target proteins before S-S reduction using isothermal titration calorimetry (ITC). Our findings indicate that Trx recognizes the oxidized form of its target proteins with exquisite selectivity, compared with their reduced counterparts. Furthermore, we show that recognition is dependent on the conformational restriction inherent to oxidized targets. Significantly, the thermodynamic signatures for multiple Trx targets reveal favorable entropic contributions as the major recognition force dictating these proteinprotein interactions. Taken together, our data afford significant new insight into the molecular forces responsible for Trx-target recognition and should aid the design of new strategies for thiol oxidoreductase inhibition.thioredoxin | redox regulation | protein-protein interactions | entropy | oxidative stress

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“…In fact, empirical calibration of the NMR-derived conformational entropy suggested that the standard approach of summing up the individual contribution of each one of the experimentally accessible bond vectors may in fact underestimate the overall contribution of conformational entropy to the binding free energy. 61 The emerging view of protein flexibility as a major source of conformational entropy that can influence the thermodynamics of binding, also supported by many other examples, 8,36 indicates that dynamic activation of protein function may be more common than thought. …”

Section: Dynamic Activation Of Protein Functionmentioning

confidence: 99%

“…Very interesting results on calmodulin have been particularly revealing about the role of conformational entropy in molecular recognition and allostery. 60,61 Calmodulin, a central player in calcium-mediated signaling, has been used as a model system to investigate the role of changes in fast (subnanosecond) internal dynamics and its associated conformational entropy in protein-ligand binding. By studying calmodulin in complex with a series of different binding peptides, it was found that the apparent change in conformational entropy was linearly related to the change in the overall binding entropy.…”

Section: Dynamic Activation Of Protein Functionmentioning

confidence: 99%

NMR reveals novel mechanisms of protein activity regulation

Kalodimos

2011

Protein Science

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NMR spectroscopy is one of the most powerful tools for the characterization of biomolecular systems. A unique aspect of NMR is its capacity to provide an integrated insight into both the structure and intrinsic dynamics of biomolecules. In addition, NMR can provide siteresolved information about the conformation entropy of binding, as well as about energetically excited conformational states. Recent advances have enabled the application of NMR for the characterization of supramolecular systems. A summary of mechanisms underpinning protein activity regulation revealed by the application of NMR spectroscopy in a number of biological systems studied in the lab is provided.

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The role of conformational entropy in molecular recognition by calmodulin

Cited by 243 publications

References 51 publications

Nonnative interactions regulate folding and switching of myristoylated protein

Nonnative interactions regulate folding and switching of myristoylated protein

A universal entropy-driven mechanism for thioredoxin–target recognition

NMR reveals novel mechanisms of protein activity regulation

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